U.S. patent application number 16/960867 was filed with the patent office on 2021-03-18 for oral drug dosage forms compromising a fixed-dose of an adhd non-stimulant and an adhd stimulant.
The applicant listed for this patent is Triastek, Inc.. Invention is credited to Senping CHENG, Feihuang DENG, Xiaoling LI, Qing LUO, Ying WANG.
Application Number | 20210077410 16/960867 |
Document ID | / |
Family ID | 1000005265916 |
Filed Date | 2021-03-18 |
United States Patent
Application |
20210077410 |
Kind Code |
A1 |
DENG; Feihuang ; et
al. |
March 18, 2021 |
ORAL DRUG DOSAGE FORMS COMPROMISING A FIXED-DOSE OF AN ADHD
NON-STIMULANT AND AN ADHD STIMULANT
Abstract
The present disclosure provides oral drug dosage forms
comprising: (a) an erodible non-stimulant material admixed with an
ADHD non-stimulant; and (b) an erodible stimulant material admixed
with an ADHD stimulant, wherein the erodible non-stimulant material
admixed with the ADHD non-stimulant is embedded in a substrate
material, and wherein upon exposure to gastrointestinal fluid the
ADHD non-stimulant is released according to a desired non-stimulant
release profile and the ADHD stimulant is released according to a
desired stimulant release profile. In some embodiment, the ADHD
non-stimulant is released according to a sustained release profile.
In some embodiments, the ADHD stimulant is released according to an
immediate release profile. The oral drug dosage forms of the
present disclosure are useful for the treatment of attention
deficit hyperactivity disorder (ADHD). Also provided herein are
methods of designing and manufacturing the oral drug dosage forms
described herein.
Inventors: |
DENG; Feihuang; (Nanjing,
CN) ; LI; Xiaoling; (Dublin, CA) ; CHENG;
Senping; (Nanjing, CN) ; WANG; Ying; (Nanjing,
CN) ; LUO; Qing; (Nanjing, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Triastek, Inc. |
Nanjing |
|
CN |
|
|
Family ID: |
1000005265916 |
Appl. No.: |
16/960867 |
Filed: |
December 25, 2018 |
PCT Filed: |
December 25, 2018 |
PCT NO: |
PCT/CN2018/123400 |
371 Date: |
July 8, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B33Y 70/00 20141201;
A61K 9/2086 20130101; A61K 31/4168 20130101; A61K 31/155 20130101;
A61K 31/4458 20130101; A61K 9/2095 20130101; A61K 31/137 20130101;
B33Y 10/00 20141201; B33Y 80/00 20141201 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/4168 20060101 A61K031/4168; A61K 31/137
20060101 A61K031/137; A61K 31/155 20060101 A61K031/155; A61K
31/4458 20060101 A61K031/4458; B33Y 80/00 20060101 B33Y080/00; B33Y
70/00 20060101 B33Y070/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 9, 2018 |
CN |
PCT/CN2018/071966 |
Claims
1. An oral drug dosage form comprising: (a) an erodible
non-stimulant material admixed with an ADHD non-stimulant; and (b)
an erodible stimulant material admixed with an ADHD stimulant,
wherein the erodible non-stimulant material admixed with the ADHD
non-stimulant is embedded in a substrate material, and wherein upon
exposure to gastrointestinal fluid the ADHD non-stimulant is
released according to a sustained release profile and the ADHD
stimulant is released according to an immediate release
profile.
2. The oral drug dosage form of claim 1, wherein the oral drug
dosage form comprises a multi-layered structure comprising a
plurality of layers of the erodible non-stimulant material admixed
with the ADHD non-stimulant.
3-4. (canceled)
5. The oral drug dosage form of claim 2, wherein each layer of the
erodible non-stimulant material admixed with the ADHD non-stimulant
of the multi-layered structure has a pre-determined surface area,
thickness, and ADHD non-stimulant mass fraction correlating with
the sustained release profile.
6. (canceled)
7. The oral drug dosage form of claim 5, wherein the surface area
of each layer of the erodible non-stimulant material admixed with
the ADHD non-stimulant of the multi-layered structure is between
about 4.5 mm.sup.2 to about 100 mm.sup.2.
8. The oral drug dosage form of claim 5, wherein each successive
layer of the erodible non-stimulant material admixed with the ADHD
non-stimulant of the multi-layered structure, proceeding from the
top layer to the bottom layer, has a smaller surface area.
9-10. (canceled)
11. The oral drug dosage form of claim 5, wherein the thickness of
each layer of the erodible non-stimulant material admixed with the
ADHD non-stimulant of the multi-layered structure is between about
0.2 mm to about 1 mm.
12. (canceled)
13. The oral drug dosage form of claim 1, wherein the substrate
material is an insulating material that is impermeable to
gastrointestinal fluid, wherein the insulating material forms a
barrier between the gastrointestinal fluid and a portion of the
erodible non-stimulant material.
14-29. (canceled)
30. The oral drug dosage form of claim 1, wherein the sustained
release profile is controlled, sustained ADHD non-stimulant release
over at least about 12 hours.
31. The oral drug dosage form of claim 1, wherein the immediate
release profile is total ADHD stimulant release within about 30
minutes.
32. The oral drug dosage form of claim 1, wherein the amount of the
ADHD non-stimulant in the oral drug dosage form is a
sub-therapeutic dose when the ADHD non-stimulant is administered
without the ADHD stimulant.
33. The oral drug dosage form of claim 1, wherein the ADHD
non-stimulant is selected from the group consisting of clonidine or
a pharmaceutically acceptable salt thereof, atomoxetine or a
pharmaceutically acceptable salt thereof, and guanfacine or a
pharmaceutically acceptable salt thereof.
34. The oral drug dosage form of claim 33, wherein the ADHD
non-stimulant is clonidine or the pharmaceutically acceptable salt
thereof and the amount of clonidine or the pharmaceutically
acceptable salt thereof in the oral drug dosage form is between
about 0.05 mg to about 0.3 mg.
35. (canceled)
36. The oral drug dosage form of claim 33, wherein the ADHD
non-stimulant is atomoxetine or the pharmaceutically acceptable
salt thereof and the amount of atomoxetine or the pharmaceutically
acceptable salt thereof in the oral drug dosage form is between
about 2.5 mg to about 100 mg.
37. (canceled)
38. The oral drug dosage form of claim 33, wherein the ADHD
non-stimulant is guanfacine or the pharmaceutically acceptable salt
thereof and the amount of guanfacine or the pharmaceutically
acceptable salt thereof in the oral drug dosage form is between
about 0.5 mg to about 4 mg.
39. (canceled)
40. The oral drug dosage form of claim 1, wherein the ADHD
stimulant is selected from the group consisting of a
methylphenidate or the pharmaceutically acceptable salt thereof,
dextromethylphenidate or a pharmaceutically acceptable salt
thereof, an amphetamine or a pharmaceutically acceptable salt
thereof, and dextroamphetamine or a pharmaceutically acceptable
salt thereof.
41. The oral drug dosage form of claim 40, wherein the ADHD
stimulant is the methylphenidate or the pharmaceutically acceptable
salt thereof and the amount of the methylphenidate or the
pharmaceutically acceptable salt thereof in the oral drug dosage
form is between about 1.75 mg to about 60 mg.
42. (canceled)
43. The oral drug dosage form of claim 40, wherein the ADHD
stimulant is dextromethylphenidate or the pharmaceutically
acceptable salt thereof and the amount of dextromethylphenidate or
the pharmaceutically acceptable salt thereof in the oral drug
dosage form is between about 1.75 mg to about 20 mg.
44-45. (canceled)
46. The oral drug dosage form of claim 40, wherein the ADHD
stimulant is dextroamphetamine or the pharmaceutically acceptable
salt thereof and the amount of dextroamphetamine or the
pharmaceutically acceptable salt thereof in the oral drug dosage
form is between about 2.5 mg to about 50 mg.
47. An oral drug dosage form comprising: (a) a multi-layered
structure comprising a plurality of layers an erodible
non-stimulant material admixed with an ADHD non-stimulant, wherein
the erodible non-stimulant material comprises hydroxyl propyl
cellulose admixed with triethyl citrate, and wherein the ADHD
non-stimulant is clonidine; and (b) an erodible stimulant material
admixed with an ADHD stimulant, wherein the erodible stimulant
material is vinylpyrrolidone-vinyl acetate copolymer admixed with
triethyl citrate, and wherein the ADHD stimulant is
dextromethylphenidate, wherein the erodible non-stimulant material
admixed with the ADHD non-stimulant is embedded in a substrate
material, and wherein upon exposure to gastrointestinal fluid the
ADHD non-stimulant is released according to a sustained release
profile and the ADHD stimulant is released according to an
immediate release profile.
48. (canceled)
49. A method for three-dimensional printing of a drug dosage form
formulated and configured to provide a sustained drug release
profile of an ADHD non-stimulant and an immediate drug release
profile of an ADHD stimulant, wherein the oral drug dosage form
comprises a multi-layered structure comprising a plurality of
layers of an erodible non-stimulant material admixed with the ADHD
non-stimulant, and wherein the erodible non-stimulant material is
embedded in a substrate material, the method comprising: (a)
dispensing the erodible non-stimulant material admixed with the
ADHD non-stimulant based on a pre-determined thickness, surface
area, and ADHD non-stimulant mass fraction; (b) dispensing an
erodible stimulant material admixed with a ADHD stimulant; and (c)
dispensing the substrate material.
50-54. (canceled)
55. A method for treating ADHD in an individual in need thereof,
the method comprising administering to the individual an oral drug
dosage form of claim 1.
56-57. (canceled)
58. The oral drug dosage form of claim 5, wherein each successive
layer of the erodible non-stimulant material admixed with the ADHD
non-stimulant of the multi-layered structure, proceeding from the
top layer to the bottom layer, has the same surface area.
Description
TECHNICAL FIELD
[0001] The present disclosure provides stable oral drug dosage
forms comprising: (a) an ADHD non-stimulant; and (b) an ADHD
stimulant, wherein the oral drug dosage forms are configured and
formulated to release the ADHD non-stimulant according to a desired
non-stimulant release profile and release the ADHD stimulant
according to a desired stimulant release profile. In some
embodiments, the ADHD non-stimulant is released according to a
sustained release profile. In some embodiments, the ADHD stimulant
is released according to an immediate release profile. Also
provided herein are methods of designing and manufacturing the oral
drug dosage forms and methods for treating ADHD.
BACKGROUND
[0002] Attention deficit hyperactivity disorder (ADHD) is a common
neurobiologic disorder characterized by age inappropriate levels of
inattention, impulsivity, and hyperactivity. ADHD was long
considered a childhood disorder, but there is growing awareness
that ADHD is also a significant source of impairment for many
teenagers and adults. The specific etiology of ADHD is unknown and
there is no cure for ADHD. Standard treatments combining
pharmacologic and behavioral therapies have demonstrated useful for
controlling the symptoms of ADHD.
[0003] ADHD stimulants act via the neurotransmitter dopamine and
are effective in reducing ADHD symptoms on a short-term basis. ADHD
stimulants are used as first-line therapy for ADHD, however, 15% of
patients do not respond optimally to monotherapy ADHD stimulant
therapy. ADHD non-stimulants, and some antidepressants, are used as
a second-line therapy for ADHD. ADHD non-stimulants act via
different chemical receptors in the brain, and although they do not
reduce ADHD symptoms quickly, the therapeutic effect can last up to
24 hours. Antidepressants, which require relatively larger doses,
are prescribed less often due to associated side effects. Thus,
there is still a need for improved ADHD treatments.
[0004] Oral medications are convenient for outpatient treatment of
ADHD, however, issues regarding, for example, administration of
multiple-active agent treatments, production of oral medications
with fixed-doses of multiple active agents, production of
multiple-active agent oral medications with individually controlled
active agent pharmacokinetics, and patient compliance are well
known in the art.
[0005] Some methods for production of multiple-active agent
fixed-dose oral medications for controlled agent release are known
in the art (see, e.g., WO2016192680, which is hereby incorporated
by reference in its entirety).
BRIEF SUMMARY
[0006] In one aspect, the present disclosure provides oral drug
dosage forms comprising: (a) an erodible non-stimulant material
admixed with an ADHD non-stimulant; and (b) an erodible stimulant
material admixed with an ADHD stimulant, wherein the erodible
non-stimulant material admixed with the ADHD non-stimulant is
embedded in a substrate material, and wherein upon exposure to
gastrointestinal fluid the ADHD non-stimulant is released according
to a sustained release profile. In some embodiments, the ADHD
stimulant is released according to an immediate release profile. In
some embodiments, the ADHD stimulant is released according to a
sustained release profile. In some embodiments, the ADHD stimulant
is released according to an immediate release profile and a
sustained release profile.
[0007] In some embodiments, the oral drug dosage form comprises a
multi-layered structure comprising a plurality of layers of the
erodible non-stimulant material admixed with the ADHD
non-stimulant. In some embodiments, the multi-layered structure
comprises at least three layers of the erodible non-stimulant
material admixed with the ADHD non-stimulant. In some embodiments,
the multi-layered structure comprises four layers of the erodible
non-stimulant material admixed with the ADHD non-stimulant. In some
embodiments, each layer of the erodible non-stimulant material
admixed with the ADHD non-stimulant of the multi-layered structure
has a pre-determined surface area, thickness, and ADHD
non-stimulant mass fraction correlating with the sustained release
profile.
[0008] In some embodiments, the surface areas of two or more layers
of the erodible non-stimulant material admixed with the ADHD
non-stimulant of the multi-layered structure are different. In some
embodiments, the surface area of each layer of the erodible
non-stimulant material admixed with the ADHD non-stimulant of the
multi-layered structure is between about 4.5 mm.sup.2 to about 100
mm.sup.2. In some embodiments, each successive layer of the
erodible non-stimulant material admixed with the ADHD non-stimulant
of the multi-layered structure, proceeding from the top layer to
the bottom layer, has a smaller surface area. In some embodiments,
each layer of the erodible non-stimulant material admixed with the
ADHD non-stimulant of the multi-layered structure is concentrically
positioned.
[0009] In some embodiments, the thicknesses of two or more layers
of the erodible non-stimulant material admixed with the ADHD
non-stimulant of the multi-layered structure are different. In some
embodiments, the thickness of each layer of the erodible
non-stimulant material admixed with the ADHD non-stimulant of the
multi-layered structure is between about 0.2 mm to about 0.7
mm.
[0010] In some embodiments, the ADHD non-stimulant mass fraction is
about 0.0001 to about 0.5.
[0011] In some embodiments, the substrate material is an insulating
material that is impermeable to gastrointestinal fluid, wherein the
insulating material forms a barrier between the gastrointestinal
fluid and a portion of the erodible non-stimulant material. In some
embodiments, the thickness of the barrier is at least about 0.2 mm.
In some embodiments, the thickness of the barrier is at least about
0.4 mm. In some embodiments, the thickness of the barrier is at
least about 1 mm.
[0012] In some embodiments, the oral drug dosage form further
comprises a layer of the substrate material that forms a substrate
rim, wherein the substrate rim forms a space, and wherein the space
is on top of the multi-layered structure. In some embodiments, the
space is not filled with a material. In some embodiments, the space
is filled with an erodible material. In some embodiments, the space
is filled with the erodible stimulant material admixed with the
ADHD stimulant.
[0013] In some embodiments, the multi-layered structure further
comprises an erodible intermediate material not admixed with the
ADHD non-stimulant, and wherein the erodible intermediate material
forms an intermediate layer between two or more layers of the
erodible non-stimulant material admixed with the ADHD non-stimulant
of the multi-layered structure.
[0014] In some embodiments, upon exposure to gastrointestinal
fluid, the erodible non-stimulant material admixed with the ADHD
non-stimulant and the erodible stimulant material admixed with the
ADHD stimulant are simultaneously exposed to gastrointestinal
fluid. In some embodiments, the erodible non-stimulant material
admixed with the ADHD non-stimulant is separated from the erodible
stimulant material admixed with the ADHD stimulant by the substrate
material.
[0015] In some embodiments, upon exposure to gastrointestinal
fluid, the erodible non-stimulant material admixed with the ADHD
non-stimulant and the erodible stimulant material admixed with the
ADHD stimulant are sequentially exposed to gastrointestinal fluid.
In some embodiments, the erodible stimulant material admixed with
the ADHD stimulant surrounds at least a portion of the erodible
non-stimulant material admixed with the ADHD non-stimulant.
[0016] In some embodiments, the erodible stimulant material admixed
with the ADHD stimulant is embedded in the substrate material.
[0017] In some embodiments, the erodible stimulant material admixed
with the ADHD stimulant is physically separated from the erodible
non-stimulant material admixed with the ADHD non-stimulant.
[0018] In some embodiments, the oral drug dosage form is configured
and formulated to provide an immediate release profile of an ADHD
stimulant. In some embodiments, the immediate release profile is
70% of the total ADHD stimulant release within about 30 minutes. In
some embodiments, the immediate release profile is 85% of the total
ADHD stimulant release within about 15 minutes.
[0019] In some embodiments, the erodible stimulant material admixed
with the ADHD stimulant is a single-layered structure. In some
embodiments, the erodible stimulant material admixed with the ADHD
stimulant has a surface area of at least about 10 mm.sup.2. In some
embodiments, the erodible stimulant material admixed with the ADHD
stimulant has a thickness of at least about 0.2 mm.
[0020] In some embodiments, the oral drug dosage form is configured
and formulated to provide a sustained release profile of an ADHD
stimulant. In some embodiments, the oral drug dosage form comprises
a multi-layered structure comprising a plurality of layers of the
erodible stimulant material admixed with the ADHD stimulant. In
some embodiments, the multi-layered structure comprises at least
three layers of the erodible stimulant material admixed with the
ADHD stimulant. In some embodiments, each layer of the erodible
stimulant material admixed with the ADHD stimulant of the
multi-layered structure has a pre-determined surface area,
thickness, and ADHD stimulant mass fraction correlating with the
sustained release profile.
[0021] In some embodiments, the oral drug dosage form comprises a
multi-layered structure comprising a plurality of layers, wherein a
first layer of the plurality of layers comprises an erodible
non-stimulant material admixed with the ADHD non-stimulant, and
wherein a second layer of the plurality of layers comprises an
erodible stimulant material admixed with the ADHD stimulant.
[0022] In some embodiments, the sustained release profile comprises
a zero-order release profile, a first-order release profile, a
delayed release profile, a pulsed release profile, an iterative
pulsed release profile, or a combination thereof. In some
embodiments, the sustained release profile is controlled, sustained
ADHD non-stimulant release over at least about 5 hours.
[0023] In some embodiments, the amount of the ADHD non-stimulant in
the oral drug dosage form is a sub-therapeutic dose when the ADHD
non-stimulant is administered without the ADHD stimulant.
[0024] In some embodiments, the ADHD non-stimulant is clonidine or
a pharmaceutically acceptable salt thereof. In some embodiments,
the amount of clonidine or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is between about 0.05 mg to
about 0.3 mg.
[0025] In some embodiments, the ADHD non-stimulant is atomoxetine
or a pharmaceutically acceptable salt thereof. In some embodiments,
the amount of atomoxetine or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is between about 2.5 mg to
about 100 mg.
[0026] In some embodiments, the ADHD non-stimulant is guanfacine or
a pharmaceutically acceptable salt thereof. In some embodiments,
the amount of guanfacine or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is between about 0.5 mg to
about 4 mg.
[0027] In some embodiments, the amount of the ADHD stimulant in the
oral drug dosage form is a sub-therapeutic dose when the ADHD
stimulant is administered without the ADHD non-stimulant.
[0028] In some embodiments, the ADHD stimulant is a methylphenidate
or the pharmaceutically acceptable salt thereof. In some
embodiments, the amount of the methylphenidate or the
pharmaceutically acceptable salt thereof in the oral drug dosage
form is between about 1.75 mg to about 60 mg. In some embodiments,
the methylphenidate is dextromethylphenidate or a pharmaceutically
acceptable salt thereof. In some embodiments, the amount of
dextromethylphenidate or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is between about 1.75 mg to
about 20 mg.
[0029] In some embodiments, the ADHD stimulant is an amphetamine.
In some embodiments, the amphetamine is dextroamphetamine or a
pharmaceutically acceptable salt thereof. In some embodiments, the
amount of dextroamphetamine or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is between about 2.5 mg to
about 50 mg.
[0030] In another aspect, the present disclosure provides oral drug
dosage forms comprising: (a) a multi-layered structure comprising a
plurality of layers an erodible non-stimulant material admixed with
an ADHD non-stimulant, wherein the erodible non-stimulant material
comprises hydroxyl propyl cellulose admixed with triethyl citrate,
and wherein the ADHD non-stimulant is clonidine; and (b) an
erodible stimulant material admixed with an ADHD stimulant, wherein
the erodible stimulant material is vinylpyrrolidone-vinyl acetate
copolymer admixed with triethyl citrate, and wherein the ADHD
stimulant is dextromethylphenidate, wherein the erodible
non-stimulant material admixed with the ADHD non-stimulant is
embedded in a substrate material, and wherein upon exposure to
gastrointestinal fluid the ADHD non-stimulant is released according
to a sustained release profile and the ADHD stimulant is released
according to an immediate release profile.
[0031] In another aspect, the present disclosure provides batches
of an oral drug dosage form described herein.
[0032] In another aspect, the present disclosure provides methods
for three-dimensional printing of a drug dosage form formulated and
configured to provide a sustained drug release profile of an ADHD
non-stimulant and an immediate drug release profile of an ADHD
stimulant, wherein the oral drug dosage form comprises a
multi-layered structure comprising a plurality of layers of an
erodible non-stimulant material admixed with the ADHD
non-stimulant, and wherein the erodible non-stimulant material is
embedded in a substrate material, the method comprising: (a)
dispensing the erodible non-stimulant material admixed with the
ADHD non-stimulant based on a pre-determined thickness, surface
area, and ADHD non-stimulant mass fraction; (b) dispensing an
erodible stimulant material admixed with a ADHD stimulant; and (c)
dispensing the substrate material.
[0033] In some embodiments, the method further comprises
determining the thickness, surface area, and drug mass fraction of
each layer of the multi-layered structure based on the sustained
drug release profile of the ADHD non-stimulant. In some
embodiments, the oral drug dosage form further comprises a layer of
the substrate material that forms a substrate rim, wherein the
substrate rim forms a space, and wherein the space is on top of the
erodible non-stimulant material admixed with the ADHD
non-stimulant. In some embodiments, the sustained drug release
profile of the ADHD non-stimulant is controlled, sustained ADHD
non-stimulant release over at least about 5 hours. In some
embodiments, the immediate drug release profile of the ADHD
stimulant is total ADHD stimulant release within about 30 minutes.
In some embodiments, the immediate drug release profile of the ADHD
stimulant is total ADHD stimulant release within about 1 hour. In
some embodiments, the ADHD non-stimulant is clonidine or a
pharmaceutically acceptable salt thereof and the ADHD stimulant is
dextromethylphenidate or a pharmaceutically acceptable salt
thereof.
[0034] In another aspect, the present disclosure provides methods
for treating ADHD in an individual in need thereof, the method
comprising administering to the individual an oral drug dosage form
described herein. In some embodiments, the oral drug dosage form is
administered once daily.
[0035] In one aspect, the present disclosure provides oral drug
dosage forms prepared by a three-dimensional printing method, the
method comprising: (a) dispensing an erodible non-stimulant
material admixed with the ADHD non-stimulant based on a
pre-determined thickness, surface area, and ADHD non-stimulant mass
fraction for each layer of a multi-layered structure comprising a
plurality of layers of the erodible non-stimulant material admixed
with the ADHD non-stimulant; (b) dispensing an erodible stimulant
material admixed with a ADHD stimulant; and (c) dispensing the
substrate material, wherein the oral drug dosage form comprises the
multi-layered structure comprising a plurality of layers of the
erodible non-stimulant material admixed with the ADHD
non-stimulant, wherein the multi-layered structure is embedded in
the substrate, and wherein upon exposure to gastrointestinal fluid
the ADHD non-stimulant is released according to a sustained release
profile and the ADHD stimulant is released according to an
immediate release profile.
[0036] These and other aspects and advantages of the present
disclosure will become apparent from the subsequent detailed
description and the appended claims. It is to be understood that
one, some, or all of the properties of the various embodiments
described herein may be combined to form other embodiments of the
present disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIGS. 1A-1C show an exemplary oral drug dosage form 100
comprising a multi-layered structure comprising a plurality of
layers 115, 120, 125 of an erodible non-stimulant material admixed
with an ADHD non-stimulant. FIG. 1A shows a cross-section view of
the exemplary oral drug dosage form 100. FIG. 1B and FIG. 1C show
external views of alternate exemplary oral drug dosage forms 101,
102 having the cross-section illustrated in FIG. 1A.
[0038] FIG. 2A and FIG. 2B show an exemplary oral drug dosage form
200. FIG. 2A shows an external view of the exemplary oral drug
dosage form 200 with translucently illustrated components to
illustrate internal components of the oral drug dosage form 200.
FIG. 2B shows a cross-section view of the exemplary dosage form
200.
[0039] FIG. 3 shows a graph of a desired drug release profile (drug
release (%) versus time (hour)).
DETAILED DESCRIPTION
[0040] The present disclosure describes oral drug dosage forms
providing individually controlled release of a fixed-dose of an
ADHD non-stimulant and a fixed-dose of an ADHD stimulant. The oral
drug dosage forms described herein may be designed and produced to
provide a desired drug release profile, or equivalent thereof, of
the ADHD non-stimulant, e.g., a sustained release profile, and a
desired drug release profile, or equivalent thereof, of the ADHD
stimulant, e.g., an immediate release profile and/or a sustained
release profile. The oral drug dosage forms of the present
disclosure may be designed for production via a three-dimensional
printing technique.
[0041] The oral drug dosage forms of the present disclosure
provide, e.g., improved dosing accuracy, treatment efficacy, and
patient compliance in comparison to traditional oral drug dosage
forms currently available on the market for the treatment of ADHD.
Furthermore, the oral drug dosage forms described herein may
provide for a reduction of: the dose of individual active
pharmaceutical ingredients in an oral drug dosage form, adverse
events, and costs associated with treatment of ADHD.
Definitions
[0042] As used herein, "ADHD stimulant" refers to a central nervous
system stimulant, or prodrug thereof, that elevates levels of
norepinephrine in an individual. Exemplary ADHD stimulants include
methylphenidate hydrochloride, dexmethylphenidate hydrochloride,
methylphenidate (d,l), dexmethylphenidate, dextroamphetamine,
dextroamphetamine sulfate, amphetamine sulfate, amphetamine
aspartate, amphetamine sulfate, dextroamphetamine saccharate,
lisdexamfetamine (prodrug), and lisdexamfetamine dimesylate.
[0043] As used herein, "ADHD non-stimulant" refers to an agent or
prodrug thereof, other than an ADHD stimulant or ADHD stimulant
prodrug, wherein the agent elevates levels of norepinephrine in an
individual. Exemplary ADHD non-stimulant include atomoxetine,
atomoxetine hydrochloride, guanfacine, guanfacine hydrochloride,
clonidine, and clonidine hydrochloride.
[0044] As used herein, the term "pharmaceutically acceptable salt"
refers to any pharmaceutically acceptable salt (e.g., acid or base)
of a compound described herein, which, upon administration to an
individual, is capable of providing the compound or an active
metabolite or residue thereof to the individual. As is known to
those of ordinary skill in the art, "salts" of the compounds
described herein may be derived from inorganic or organic acids and
bases. Examples of acids include, but are not limited to,
hydrochloric, hydrobromic, sulfinuric, nitric, perchloric, fumaric,
maleic, phosphoric, glycolic, lactic, salicylic, succinic,
toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,
ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,
benzenesulfonic acid, and the like. Other acids, such as oxalic,
while not in themselves pharmaceutically acceptable, may be
employed in the preparation of salts useful as intermediates in
obtaining the compounds described herein and their pharmaceutically
acceptable acid addition salts.
[0045] As used herein, "treat," "treatment," or "treating" is an
approach for obtaining beneficial or desired results including
clinical results. For purposes of this disclosure, beneficial or
desired clinical results include, but are not limited to, one or
more of the following: alleviating one or more symptoms resulting
from the disease, decreasing the dose of one or more other
medications required to treat the disease, and/or increasing the
quality of life.
[0046] As used herein, the term "effective amount" refers to an
amount of a compound or composition sufficient to treat a specified
disorder, condition, or disease, such as ameliorate, palliate,
lessen, and/or delay one or more of the symptoms of the
disease.
[0047] As used herein, the term "individual" refers to a mammal and
includes, but is not limited to, human, bovine, horse, feline,
canine, rodent, or primate. In some embodiments, the individual is
human.
[0048] The term "comprises" and grammatical equivalents thereof are
used herein to mean that other components, ingredients, steps, etc.
are optionally present. For example, an article "comprising"
components A, B, and C may consist of (i.e., contain only)
components A, B, and C, or may contain not only components A, B,
and C but also one or more other components. It is understood that
"comprises" and grammatical equivalents thereof include "consisting
of" and "consisting essentially of."
[0049] Where a range of values is provided, it is understood that
each intervening value, to the hundredth of the unit of the lower
limit, unless the context clearly dictates otherwise, between the
upper and lower limit of that range and any other stated or
intervening value in that stated range, is encompassed within the
disclosure (subject to any specifically excluded limit in the
stated range). Where the stated range includes one or both of the
limits, ranges excluding either or both of those included limits
are also included in the disclosure.
[0050] Reference to "about" a value or parameter herein includes
(and describes) variations that are directed to that value or
parameter per se. For example, description referring to "about X"
includes a description of "X."
[0051] As used herein, the singular forms "a," "or," and "the"
include plural referents unless the context clearly dictates
otherwise.
Oral Drug Dosage Forms
[0052] The present disclosure provides oral drug dosage form
comprising: (a) an erodible non-stimulant material admixed with an
ADHD non-stimulant; and (b) an erodible stimulant material admixed
with an ADHD stimulant, wherein the erodible non-stimulant material
admixed with the ADHD non-stimulant is embedded in a substrate
material, and wherein upon exposure to gastrointestinal fluid the
ADHD non-stimulant is released according to a sustained release
profile and the ADHD stimulant is released according to a desired
release profile. In some embodiments, the ADHD stimulant is
released according to an immediate release profile. In some
embodiments, the stimulant is released according to an immediate
release profile and/or a sustained release profile.
[0053] In some embodiments, upon exposure to gastrointestinal
fluid, the erodible non-stimulant material admixed with the ADHD
non-stimulant and the erodible stimulant material admixed with the
ADHD stimulant are simultaneously exposed to gastrointestinal
fluid. In some embodiments, the erodible non-stimulant material
admixed with the ADHD non-stimulant is separated from the erodible
stimulant material admixed with the ADHD stimulant by a substrate
material. In some embodiments, upon exposure to gastrointestinal
fluid, the erodible non-stimulant material admixed with the ADHD
non-stimulant and the erodible stimulant material admixed with the
ADHD stimulant are sequentially exposed to gastrointestinal fluid.
In some embodiments, upon exposure to gastrointestinal fluid, the
erodible non-stimulant material admixed with the ADHD non-stimulant
and the erodible stimulant material admixed with the ADHD stimulant
are sequentially exposed to gastrointestinal fluid, wherein upon
exposure to gastrointestinal fluid, the ADHD stimulant is released
from the oral drug dosage form first. In some embodiments, the
erodible non-stimulant material admixed with the ADHD non-stimulant
and the erodible stimulant material admixed with the ADHD stimulant
are configured as one or more layers of a multi-layered structure.
In some embodiments, the erodible stimulant material admixed with
the ADHD stimulant surrounds at least a portion of the erodible
non-stimulant material admixed with the ADHD non-stimulant. In some
embodiments, upon exposure to gastrointestinal fluid, the erodible
non-stimulant material admixed with the ADHD non-stimulant and the
erodible stimulant material admixed with the ADHD stimulant are
sequentially exposed to gastrointestinal fluid, wherein upon
exposure to gastrointestinal fluid, the ADHD non-stimulant is
released from the oral drug dosage form first.
[0054] In some embodiments, the oral drug dosage form is an
integrated dosage form (e.g., materials of the dosage form do not
form components that may be readily separated).
[0055] The oral drug dosage forms described herein may be, for
example, any size, shape, or weight that is suitable for oral
administration. In some embodiments, the oral drug dosage form is
suitable for oral administration to an individual, wherein the
size, shape, and/or weight of the oral drug dosage form is based on
an attribute of the individual. In some embodiments, the attribute
of an individual is one or more of height, weight, or age. In some
embodiments, the individual is an infant. In some embodiments, the
individual is a child. In some embodiments, the individual is an
adolescent. In some embodiments, the individual is an adult.
[0056] The oral drug dosage form described herein may be a
personalized oral drug dosage form, wherein the personalized drug
dosage form is tailored based on a patient's need(s). In some
embodiments, the sustained release profile of an ADHD non-stimulant
of an oral drug dosage form is adjusted, wherein the sustained
release profile is based on a need of the patient. In some
embodiments, the amount of an ADHD non-stimulant of an oral drug
dosage form is adjusted, wherein the amount of the ADHD
non-stimulant is based on a need of the patient. In some
embodiments, the amount of an ADHD stimulant of an oral drug dosage
form is adjusted, wherein the amount of the ADHD stimulant is based
on a need of the patient. In some embodiments, the amount of an
ADHD non-stimulant and the amount of an ADHD stimulant of an oral
drug dosage form are adjusted, wherein the amount of the ADHD
non-stimulant and the amount of ADHD stimulant is based on a need
of the patient. In some embodiments, the amount of an ADHD
stimulant and/or an ADHD non-stimulant is determined by titrating
the amount of the ADHD stimulant and/or the ADHD non-stimulant.
[0057] In some embodiments, the largest dimension crossing an oral
drug dosage form, e.g., largest diameter, is about 1 mm to about 25
mm, such as any of about 2 mm to about 10 mm, about 5 mm to about
12 mm, about 8 mm to about 15 mm, about 5 mm to about 10 mm, or
about 7 mm to about 9 mm. In some embodiments, the largest
dimension crossing an oral drug dosage form, e.g., largest
diameter, is less than about 25 mm, such as less than about any of
24 mm, 23 mm, 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15
mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5
mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the largest
dimension crossing an oral drug dosage form, e.g., largest
diameter, is greater than about 1 mm, such as greater than about
any of 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11
mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm,
21 mm, 22 mm, 23 mm, 24 mm, or 25 mm. In some embodiments, the
largest dimension crossing an oral drug dosage form, e.g., largest
diameter, is about any of 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm,
8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm,
18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm.
[0058] In some embodiments, the oral drug dosage form has a
thickness of about 1 mm to about 25 mm, such as any of about 2 mm
to about 10 mm, about 5 mm to about 12 mm, about 8 mm to about 15
mm, about 5 mm to about 10 mm, or about 7 mm to about 9 mm. In some
embodiments, the oral drug dosage form has a thickness of less than
about 25 mm, such as less than about any of 24 mm, 23 mm, 22 mm, 21
mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm,
11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1
mm. In some embodiments, the oral drug dosage form has a thickness
of greater than about 1 mm, such as greater than about any of 2 mm,
3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13
mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm,
23 mm, 24 mm, or 25 mm. In some embodiments, the oral drug dosage
form has a thickness of about any of 1 mm, 2 mm, 3 mm, 4 mm, 5 mm,
6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm,
16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or
25 mm.
[0059] In some embodiments, the shape of an oral drug dosage form
comprises a cylinder, oval, bullet shape, arrow head shape,
triangle, arced triangle, square, arced square, rectangle, arced
rectangle, diamond, pentagon, hexagon, octagon, half moon, almond,
or a combination thereof.
[0060] In some embodiments, the shape of an oral drug dosage form
comprises a cylinder, oval, bullet shape, arrow head shape,
triangle, arced triangle, square, arced square, rectangle, arced
rectangle, diamond, pentagon, hexagon, octagon, half moon, almond,
or a combination thereof, wherein the largest dimension crossing
the oral drug dosage form, e.g., largest diameter, is about any of
1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm,
12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21
mm, 22 mm, 23 mm, 24 mm, or 25 mm.
[0061] In some embodiments, the total weight of an oral drug dosage
form is about 20 mg to about 1500 mg, such as about any of about 50
mg to about 150 mg, about 150 mg to about 250 mg, about 160 mg to
about 170 mg, about 250 mg to about 350 mg, about 350 mg to about
450 mg, about 450 mg to about 550 mg, about 550 mg to about 650 mg,
about 650 mg to about 750 mg, about 750 mg to about 850 mg, about
850 mg to about 950 mg, about 950 mg to about 1050 mg, about 1050
mg to about 1150 mg, about 1150 mg to about 1250 mg, about 1250 mg
to about 1350 mg, or about 1350 mg to about 1450 mg. In some
embodiments, the total weight of an oral drug dosage form is less
than about 1500 mg, such as less than about any of 1450 mg, 1400
mg, 1350 mg, 1300 mg, 1250 mg, 1200 mg, 1150 mg, 1100 mg, 1050 mg,
1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg,
600 mg, 550 mg, 500 mg, 475 mg, 450 mg, 425 mg, 400 mg, 375 mg, 350
mg, 325 mg, 300 mg, 275 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg,
125 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60
mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, or 25 mg. In some
embodiments, the total weight of an oral drug dosage form is
greater than about 20 mg, such as greater than about any of 30 mg,
35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80
mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,
225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425
mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg,
800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,
1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, or 1450 mg. In some
embodiments, the total weight of an oral drug dosage form is about
any of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60
mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125
mg, 150 mg, 160 mg, 165 mg, 170 mg, 175 mg, 200 mg, 225 mg, 250 mg,
275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475
mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg,
900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250
mg, 1300 mg, 1350 mg, 1400 mg, or 1450 mg.
[0062] The oral drug dosage forms of the present disclosure can
further be coated, such as embedded, encased, or attached thereto,
to, for example, (a) modify the taste, odor, and/or color of the
oral drug dosage form; (b) protect the components of the oral drug
dosage form from light, moisture, and/or air; (c) control the
release of the components of the oral drug dosage form; (d) improve
and/or alter the external appearance of the oral drug dosage form;
(e) adjust position of drug release; (f) adjust texture of the oral
drug dosage form; and (g) provide abuse deterrent features to the
oral drug dosage form. In some embodiments, at least a portion of
an oral drug dosage form is coated, such as embedded, encased, or
attached thereto. In some embodiments, the oral drug dosage form is
coated, such as embedded, encased, or attached thereto, with a
sugar coating, e.g., an erodible material comprising sugar. In some
embodiments, the oral drug dosage form is coated, such as embedded,
encased, or attached thereto, with a film. In some embodiments, the
oral drug dosage form is coated, such as embedded, encased, or
attached thereto, with an enteric coating. In some embodiments, the
oral drug dosage form is coated, such as embedded, encased, or
attached thereto, with a gelatin layer.
[0063] In some embodiments, the oral drug dosage form has a surface
area of about 20 mm.sup.2 to about 700 mm.sup.2. In some
embodiments, the oral drug dosage form has a surface area of at
least about 20 mm.sup.2, such as at least about any of 30 mm.sup.2,
40 mm.sup.2, 50 mm.sup.2, 60 mm.sup.2, 70 mm.sup.2, 80 mm.sup.2, 90
mm.sup.2, 100 mm.sup.2, 125 mm.sup.2, 150 mm.sup.2, 175 mm.sup.2,
200 mm.sup.2, 225 mm.sup.2, 250 mm.sup.2, 275 mm.sup.2, 300
mm.sup.2, 325 mm.sup.2, 350 mm.sup.2, 375 mm.sup.2, 400 mm.sup.2,
425 mm.sup.2, 450 mm.sup.2, 475 mm.sup.2, 500 mm.sup.2, 525
mm.sup.2, 550 mm.sup.2, 575 mm.sup.2, 600 mm.sup.2, 625 mm.sup.2,
650 mm.sup.2, 675 mm.sup.2, or 700 mm.sup.2. In some embodiments,
the oral drug dosage form has a surface area of less than about 700
mm.sup.2, such as less than about any of 675 mm.sup.2, 650
mm.sup.2, 625 mm.sup.2, 600 mm.sup.2, 575 mm.sup.2, 550 mm.sup.2,
525 mm.sup.2, 500 mm.sup.2, 475 mm.sup.2, 450 mm.sup.2, 425
mm.sup.2, 400 mm.sup.2, 375 mm.sup.2, 350 mm.sup.2, 325 mm.sup.2,
300 mm.sup.2, 275 mm.sup.2, 250 mm.sup.2, 225 mm.sup.2, 200
mm.sup.2, 175 mm.sup.2, 150 mm.sup.2, 125 mm.sup.2, 100 mm.sup.2,
90 mm.sup.2, 80 mm.sup.2, 70 mm.sup.2, 60 mm.sup.2, 50 mm.sup.2, 40
mm.sup.2, or 30 mm.sup.2. In some embodiments, the oral drug dosage
form has a surface area of about any of 700 mm.sup.2, 675 mm.sup.2,
650 mm.sup.2, 625 mm.sup.2, 600 mm.sup.2, 575 mm.sup.2, 550
mm.sup.2, 525 mm.sup.2, 500 mm.sup.2, 475 mm.sup.2, 450 mm.sup.2,
425 mm.sup.2, 400 mm.sup.2, 375 mm.sup.2, 350 mm.sup.2, 325
mm.sup.2, 300 mm.sup.2, 275 mm.sup.2, 250 mm.sup.2, 225 mm.sup.2,
200 mm.sup.2, 175 mm.sup.2, 150 mm.sup.2, 125 mm.sup.2, 100
mm.sup.2, 90 mm.sup.2, 80 mm.sup.2, 70 mm.sup.2, 60 mm.sup.2, 50
mm.sup.2, 40 mm.sup.2, 30 mm.sup.2, or 20 mm.sup.2.
A. Erodible Non-Stimulant Materials Admixed with an ADHD
Non-Stimulant
[0064] The oral drug dosage forms described herein comprise an
erodible non-stimulant material admixed with an ADHD non-stimulant,
wherein the ADHD non-stimulant is released from the oral drug
dosage form according to a sustained release profile. Generally,
the erosion of an erodible non-stimulant material admixed with an
ADHD non-stimulant correlates with the release rate of the ADHD
non-stimulant from an oral drug dosage form.
[0065] In some embodiments, the oral drug dosage form comprises a
multi-layered structure comprising a plurality of layers of an
erodible non-stimulant material admixed with an ADHD non-stimulant.
In some embodiments, erosion of a multi-layered structure
comprising a plurality of layers of an erodible non-stimulant
material admixed with an ADHD non-stimulant correlates with the
release of the ADHD non-stimulant from an oral drug dosage form,
wherein the ADHD non-stimulant is released from the oral drug
dosage form according to a sustained release profile. For example,
a multi-layered structure is illustrated in the oral drug dosage
form 100 of FIG. 1A. The exemplary multi-layered structure contains
three layers 115, 120, 125 of an erodible non-stimulant material
admixed with an ADHD non stimulant embedded in a substrate material
110 (FIG. 1A). The multi-layered structures described herein may
comprise any number of layers. In some embodiments, the
multi-layered structure comprises at least three layers of an
erodible non-stimulant material admixed with an ADHD non-stimulant.
In some embodiments, the multi-layered structure comprises 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 layers of
an erodible non-stimulant material admixed with an ADHD
non-stimulant.
[0066] In some embodiments, each layer of an erodible non-stimulant
material admixed with an ADHD non-stimulant of a multi-layered
structure has a pre-determined surface area, thickness, and ADHD
non-stimulant mass fraction correlating with a sustained release
profile of the ADHD non-stimulant material.
[0067] The surface area of a layer refers to the area of the
surface of the layer exposed upon exposure to gastrointestinal
fluid. For example, as illustrated in FIG. 1B, the top surface of
the top layer (the layer first exposed to gastrointestinal fluid
upon oral administration) of the multi-layered structure 155 of the
oral drug dosage form 101 is exposed to gastrointestinal fluid
following oral administration and represents the surface area of
the top layer (e.g., the top layer 115 shown in the exemplary cross
section view of FIG. 1A). In some embodiments, the surface areas of
two or more layers of an erodible non-stimulant material admixed
with an ADHD non-stimulant of a multi-layered structure are
different. In some embodiments, the surface area of each layer of
an erodible non-stimulant material admixed with an ADHD
non-stimulant of a multi-layered structure is between about 1
mm.sup.2 to about 100 mm.sup.2, such as any of about 3 mm.sup.2 to
about 26 mm.sup.2, or about 4.5 mm.sup.2 to about 51 mm.sup.2. In
some embodiments, the surface area of each layer of an erodible
non-stimulant material admixed with an ADHD non-stimulant of a
multi-layered structure is at least about 10 mm.sup.2, such as at
least about any of 20 mm.sup.2, 30 mm.sup.2, 40 mm.sup.2, 50
mm.sup.2, 60 mm.sup.2, or 70 mm.sup.2.
[0068] In some embodiments, each successive layer of an erodible
non-stimulant material admixed with the ADHD non-stimulant of a
multi-layered structure, proceeding from the top to the bottom of
the multi-layered structure, has a smaller surface area. The top of
a multi-layered structure refers to a layer of an erodible
non-stimulant material admixed with an ADHD non-stimulant of the
multi-layered structure that is first contacted with
gastrointestinal fluid upon oral administration. In preferred
embodiments, the complete surface area of a successive layer of a
multi-layered structure will be completely exposed to
gastrointestinal fluid after a layer above has been fully eroded by
gastrointestinal fluid. For example, as shown in FIG. 1A, when the
top layer 115 of the multi-layered structure erodes, the complete
surface area of the second layer 120 will be exposed to
gastrointestinal fluid (the dashed line 121 indicates the
cross-section view of the surface area of the second layer. In some
embodiments, each layer of an erodible non-stimulant material
admixed with an ADHD non-stimulant of a multi-layered structure is
concentrically positioned.
[0069] The thickness of a layer is measured substantially in line
with the direction of erosion of an erodible material from a
surface that will first be exposed to a gastrointestinal fluid. For
example, the thickness of a layer, e.g., 120, of a multi-layered
structure is measured substantially in line with the direction of
erosion 130 (the thickness of layer 120 is indicated by the dashed
bracket 135) (FIG. 1A). In some embodiments, the thickness of a
layer can be any thickness, such as a thickness suitable for
production by 3D printing. In some embodiments, the thicknesses of
two or more layers of an erodible non-stimulant material admixed
with an ADHD non-stimulant of a multi-layered structure are
different. In some embodiments, the thicknesses of two or more
layers of an erodible non-stimulant material admixed with an ADHD
non-stimulant of a multi-layered structure are the same.
[0070] In some embodiments, the thickness of each layer of an
erodible non-stimulant material admixed with an ADHD non-stimulant
of a multi-layered structure is between about 0.05 mm to about 1
mm, such as between about 0.1 mm to about 0.7 mm. In some
embodiments, the thickness of a layer of an erodible non-stimulant
material admixed with an ADHD non-stimulant of a multi-layered
structure is less than about 1.0 mm, such as less than about any of
0.95 mm, 0.9 mm, 0.85 mm, 0.8 mm, 0.75 mm, 0.7 mm, 0.65 mm, 0.6 mm,
0.55 mm, 0.5 mm, 0.45 mm, 0.4 mm, 0.35 mm, 0.3 mm, 0.25 mm, 0.2 mm,
0.15 mm, 0.1 mm, or 0.05 mm. In some embodiments, the thickness of
a layer of an erodible non-stimulant material admixed with an ADHD
non-stimulant of a multi-layered structure is greater than about
0.01 mm, such as greater than about any of 0.05 mm, 0.1 mm, 0.15
mm, 0.2 mm, 0.25 mm, 0.3 mm, 0.35 mm, 0.4 mm, 0.45 mm, 0.5 mm, 0.55
mm, 0.6 mm, 0.65 mm, 0.7 mm, 0.75 mm, 0.8 mm, 0.85 mm, 0.9 mm, 0.95
mm, or 1 mm. In some embodiments, the thickness of a layer of an
erodible non-stimulant material admixed with an ADHD non-stimulant
of a multi-layered structure is about any of 0.65 mm, 0.52 mm, or
0.26 mm.
[0071] The drug mass fraction of a layer is the mass of the drug,
e.g., an ADHD non-stimulant, in the layer of the erodible material
admixed with the drug divided by the total mass of the layer of the
erodible material admixed with the drug. In some embodiments, the
drug mass faction of a layer of an erodible non-stimulant material
admixed with an ADHD non-stimulant is at least about 0.0001, such
as at least about any of 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03,
0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3,
0.35, 0.4, 0.45, or 0.5. In some embodiments, the drug mass faction
of a layer of an erodible non-stimulant material admixed with an
ADHD non-stimulant is about any of 0.0001, 0.0005, 0.001, 0.005,
0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15,
0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5. In some embodiments, the
drug mass fractions of two or more layers of an erodible
non-stimulant material admixed with an ADHD non-stimulant of a
multi-layered structure are the same. In some embodiments, the drug
mass fractions of two or more layers of an erodible non-stimulant
material admixed with an ADHD non-stimulant of a multi-layered
structure are different.
[0072] In some embodiments, the multi-layered structure comprises a
top layer of a first erodible non-stimulant material admixed with
an ADHD non-stimulant and another layer of a second erodible
non-stimulant material admixed with the ADHD non-stimulant. In some
embodiments, the multi-layered structure comprises a top layer of a
first erodible non-stimulant material admixed with an ADHD
non-stimulant and all other layers of a second erodible
non-stimulant material admixed with the ADHD non-stimulant. In some
embodiments, the first erodible non-stimulant material and the
second erodible non-stimulant material are the same. In some
embodiments, the first erodible non-stimulant material and the
second erodible non-stimulant material are different. In some
embodiments, the first erodible non-stimulant material and the
second erodible non-stimulant material are different, wherein the
erosion rate of the first erodible non-stimulant material is slower
than the second erodible non-stimulant material.
i. Sustained Release Profiles
[0073] The oral drug dosage forms described herein provide release
of an ADHD non-stimulant according to a sustained release profile.
In some embodiments, the oral drug dosage forms described herein
provide controlled (e.g., desired) release of an ADHD non-stimulant
over at least about 4 hours, such as at least about any of 5 hours,
6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours,
13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19
hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some
embodiments, the oral drug dosage forms described herein provide
controlled (e.g., desired) release of an ADHD non-stimulant over
about any of 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours,
10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16
hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours,
23 hours, or 24 hours.
[0074] In some embodiments, the sustained release profile comprises
a zero-order release profile, a first-order release profile, a
delayed release profile, a pulsed release profile, an iterative
pulsed release profile, or a combination thereof.
[0075] In some embodiments, the sustained release profile is
similar, e.g., equivalent or bioequivalent, to a desired drug
release profile or a release profile of a reference oral drug
dosage form. The release profile, e.g., sustained release profile,
of an oral drug dosage form may be evaluated using an in vitro
dissolution rate of the oral drug dosage form. In some embodiments,
the desired drug release profile, e.g., sustained release profile,
of an oral drug dosage form is similar, e.g., equivalent or
bioequivalent, to the in vitro dissolution rate of the oral drug
dosage form. In some embodiments, the desired drug release profile
of an oral drug dosage form is similar, e.g., equivalent or
bioequivalent, to the in vivo drug release profile of the oral drug
dosage form. In some embodiments, the in vivo drug release profile
of an oral drug dosage form is based on evaluation of the in vitro
dissolution rate of the oral drug dosage form. In some embodiments,
the desired drug release profile of an oral drug dosage form is
similar, e.g., equivalent or bioequivalent, to the release profile
of a reference oral drug dosage form. Methods for in vitro
dissolution testing and determining dissolution similarity are
known in the art and the U.S. Food and Drug Administration has
provided industry guidance on such methods (see Guidance for
Industry; Dissolution Testing of Immediate Release Solid Oral
Dosage Forms; CDER; August 1997).
[0076] Methods for in vitro dissolution testing include a
logarithmic curve method, probability unit method, exponential
model method, Weibull method, and Gompertz method. Statistical
analysis methods for determining dissolution similarity of two
dissolution profiles, e.g., an experimentally determined
dissolution profile and a desired drug release profile, comprise
regression analysis, ANOVA, similarity factor method, varying
factor method, Splitpolt method, and Chow's method. In some
embodiments, the dissolution similarity is evaluated using the
similarity factor. In some embodiments, the dissolution similarity
is evaluated using Chow's method.
[0077] In some embodiments, the release of the ADHD non-stimulant
or ADHD stimulant is measured at one or more of about pH 2, about
pH 7.0, and about pH 4.5.
[0078] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 20% to about 30% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 35% to about 45% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 60% to about 70% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 75% to about 85% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 90% to about 100% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 95% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
[0079] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 21% to about 29% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 36% to about 44% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 61% to about 69% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 76% to about 84% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 91% to about 99% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 96% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
[0080] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 22% to about 28% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 37% to about 43% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 62% to about 68% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 77% to about 83% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 92% to about 98% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 97% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
[0081] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 23% to about 27% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 38% to about 42% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 63% to about 67% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 78% to about 82% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 93% to about 97% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 98% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
[0082] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 24% to about 26% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 39% to about 41% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 64% to about 66% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 79% to about 81% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 94% to about 96% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 99% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
[0083] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 24% to about 28% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 41% to about 45% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 63% to about 67% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 78% to about 82% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 95% to about 99% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 98% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
[0084] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 22% to about 26% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 38% to about 42% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 61% to about 65% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 75% to about 79% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 93% to about 97% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 98% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
[0085] In some embodiments, the oral drug dosage form releases an
ADHD non-stimulant according to one or more of the following
criteria: (i) about 18% to about 22% of the total ADHD
non-stimulant is released at 1 hour after administration; (ii)
about 32% to about 36% of the total ADHD non-stimulant is released
at 2 hours after administration; (iii) about 51% to about 55% of
the total ADHD non-stimulant is released at 4 hours after
administration; (iv) about 67% to about 71% of the total ADHD
non-stimulant is released at 6 hours after administration; (v)
about 89% to about 93% of the total ADHD non-stimulant is released
at 10 hours after administration; and (vi) about 98% to about 100%
of the total ADHD non-stimulant is released at 12 hours after
administration.
ii. ADHD Non-Stimulants
[0086] The oral drug dosage forms described herein comprise an
erodible non-stimulant material admixed with an ADHD non-stimulant.
ADHD non-stimulants act by, e.g., (i) selectively inhibiting
presynaptic norepinephrine transporters with secondary effects on
dopaminergic systems (e.g., atomoxetine); (ii) selectively
stimulating .alpha..sub.2A-adrenergic receptors in the prefrontal
cortex (e.g., guanfacine), and (iii) stimulating central
.alpha..sub.2A-adrenergic receptors to reduce sympathetic outflow
(e.g., clonidine).
[0087] In some embodiments, the ADHD non-stimulant is a
serotonin-norepinephrine reuptake inhibitor. In some embodiments,
the ADHD non-stimulant is a dopamine transporter inhibitor. In some
embodiments, the ADHD non-stimulant is a norepinephrine transporter
inhibitor. In some embodiments, the ADHD non-stimulant is a
serotonin transporter inhibitor. In some embodiments, the ADHD
non-stimulant is an .alpha..sub.2 adrenergic agonist. In some
embodiments, the ADHD non-stimulant is an imidazoline receptor
agonist.
[0088] In some embodiments, the ADHD non-stimulant is atomoxetine
((R)--N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine), guanfacine,
clonidine, or a pharmaceutically acceptable salt thereof, including
atomoxetine HCl, guanfacine HCl, or clonidine HCl, or a combination
thereof. In some embodiments, the ADHD non-stimulant is clonidine.
In some embodiments, the ADHD non-stimulant is atomoxetine. In some
embodiments, the ADHD non-stimulant is guanfacine.
[0089] In some embodiments, the oral drug dosage form comprises 2
or more ADHD non-stimulants. In some embodiments, the oral drug
dosage form comprises clonidine and atomoxetine. In some
embodiments, the oral drug dosage form comprises clonidine and
guanfacine. In some embodiments, the oral drug dosage form
comprises atomoxetine and guanfacine.
[0090] In some embodiments, the amount of an ADHD non-stimulant in
an oral drug dosage form is a sub-therapeutic dose when the ADHD
non-stimulant is not administered in conjunction with an ADHD
stimulant.
[0091] In some embodiments, the amount of an ADHD non-stimulant in
an oral drug dosage form is about 0.05 to about 110 mg, such as
about 0.05 mg to about 0.25 mg, about 0.1 mg to about 0.2 mg, about
0.5 mg to about 5 mg, about 1 mg to about 4 mg, about 5 mg to about
110 mg, about 10 mg to about 100 mg, about 10 mg to about 25 mg,
about 15 mg to about 60 mg, about 18 mg to about 80 mg, about 40 mg
to about 80 mg, or about 40 mg to about 60 mg. In some embodiments,
the amount of an ADHD non-stimulant in an oral drug dosage form is
less than about 110 mg, such as less than about any of 100 mg, 95
mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg,
45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 18 mg, 15 mg, 10 mg, 9
mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.5 mg, 0.4 mg,
0.3 mg, 0.2 mg, 0.1 mg, or 0.05 mg. In some embodiments, the amount
of an ADHD non-stimulant in an oral drug dosage form is greater
than about 0.05 mg, such as greater than about any of 0.1 mg, 0.2
mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7
mg, 8 mg, 9 mg, 10 mg, 15 mg, 18 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40
mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg,
90 mg, 95 mg, 100 mg, or 110 mg. In some embodiments, the amount of
an ADHD non-stimulant in an oral drug dosage form is about 0.05 mg,
0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5
mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 18 mg, 20 mg, 25 mg, 30
mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg,
80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or 110 mg.
[0092] In some embodiments, the ADHD non-stimulant of an oral drug
dosage form is clonidine or a pharmaceutically acceptable salt
thereof, wherein the amount of clonidine or the pharmaceutically
acceptable salt thereof in the oral drug dosage form is between
about 0.05 mg to about 0.3 mg. In some embodiments, the ADHD
non-stimulant of an oral drug dosage form is clonidine or a
pharmaceutically acceptable salt thereof, wherein the amount of
clonidine or the pharmaceutically acceptable salt thereof in the
oral drug dosage form is about any of 0.05 mg, 0.1 mg, 0.15 mg, 0.2
mg, 0.25 mg, or 0.3 mg.
[0093] In some embodiments, the ADHD non-stimulant of an oral drug
dosage form is atomoxetine or a pharmaceutically acceptable salt
thereof, wherein the amount of atomoxetine or the pharmaceutically
acceptable salt thereof in the oral drug dosage form is between
about 2.5 mg to about 100 mg. In some embodiments, the ADHD
non-stimulant of an oral drug dosage form is atomoxetine or a
pharmaceutically acceptable salt thereof, wherein the amount of
atomoxetine or the pharmaceutically acceptable salt thereof in the
oral drug dosage form is about any of 2.5 mg, 5 mg, 7.5 mg, 10 mg,
15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60
mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg.
[0094] In some embodiments, the ADHD non-stimulant of an oral drug
dosage form is guanfacine or a pharmaceutically acceptable salt
thereof, wherein the amount of guanfacine or the pharmaceutically
acceptable salt thereof in the oral drug dosage form is between
about 0.5 mg to about 4 mg. In some embodiments, the ADHD
non-stimulant of the oral drug dosage form is guanfacine or a
pharmaceutically acceptable salt thereof, wherein the amount of
guanfacine or the pharmaceutically acceptable salt thereof in the
oral drug dosage form is about any of 0.5 mg, 0.75 mg, 1 mg, 1.5
mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, or 4 mg.
[0095] Those of ordinary skill in the art will recognize that the
provided list of ADHD non-stimulants and dosages is not limiting
and recognize additional ADHD non-stimulant pharmaceuticals and
dosages which will be useful with embodiments of the present
disclosure.
B. Intermediate Layers
[0096] In some embodiments, the oral drug dosage forms comprising
an ADHD non-stimulant described herein comprise a multi-layered
structure further comprising an intermediate layer of an erodible
intermediate material not admixed with the ADHD non-stimulant. In
some embodiments, the intermediate layer is on top of the top layer
of an erodible non-stimulant material admixed with an ADHD
non-stimulant of a multi-layered structure.
[0097] In some embodiments, the oral drug dosage forms comprising
an ADHD non-stimulant described herein comprise a multi-layered
structure further comprising an erodible intermediate material not
admixed with the ADHD non-stimulant, wherein the erodible
intermediate material forms an intermediate layer between two or
more layers of an erodible non-stimulant material admixed with the
ADHD non-stimulant of the multi-layered structure. In some
embodiments, the intermediate layer is between the top layer of an
erodible non-stimulant material admixed with an ADHD on-stimulant
material of a multi-layered structure and a subsequent layer of the
erodible non-stimulant material admixed with the ADHD
non-stimulant.
[0098] In some embodiments, the intermediate layer may modulate the
release profile of a drug of an oral drug dosage form. In some
embodiments, the oral drug dosage form comprising an intermediate
layer has a delayed release profile or a pulsatile release
profile.
C. Erodible Stimulant Materials Admixed with an ADHD Stimulant
[0099] The oral drug dosage forms described herein comprise an
erodible stimulant material admixed with an ADHD stimulant, wherein
the ADHD stimulant is released from the oral drug dosage form
according to a desired stimulant release profile. Generally, the
erosion of an erodible stimulant material admixed with an ADHD
stimulant correlates with the release rate of the ADHD stimulant
from an oral drug dosage form. The ADHD stimulant may be released
according to any desired release profile, which may encompass the
combination of two or more release profiles. In some embodiments,
the ADHD stimulant is released from the oral drug dosage form
according to an immediate release profile. In some embodiments, the
ADHD stimulant is released from the oral drug dosage form according
to a sustained release profile. In some embodiments, the ADHD
stimulant is released from the oral drug dosage form according to
an immediate release profile and a sustained release profile.
[0100] In some embodiments, the immediate release profile of an
ADHD stimulant of an oral drug dosage form described herein is
substantially similar to the release profile of the reference ADHD
stimulant. In some embodiments, the immediate release profile of an
ADHD stimulant of an oral drug dosage form described herein
conforms with a release profile as measured via in vitro
dissolution testing, e.g., releasing at least 85% or more of the
total drug from the oral drug dosage form in 15 minutes in one or
more or the following media: (1) 0.1 N HCl or Simulated Gastric
Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8
buffer or Simulated Intestinal Fluid USP without enzymes.
[0101] In some embodiments, the erodible stimulant material admixed
with an ADHD stimulant is embedded in a substrate material.
[0102] In some embodiments, the erodible stimulant material admixed
with an ADHD stimulant coats or contacts at least a portion of a
substrate material or a multi-layered structure comprising a
plurality of layers of an erodible non-stimulant material admixed
with an ADHD non-stimulant.
[0103] In some embodiments, the erodible stimulant material admixed
with an ADHD stimulant is a single-layered structure. In some
embodiments, the erodible stimulant material admixed with an ADHD
stimulant is a single-layered structure, wherein the single-layered
structure has a pre-determined surface area, thickness, and ADHD
stimulant mass fraction correlating with a desired release profile
of the ADHD stimulant. In some embodiments, the erodible stimulant
material admixed with an ADHD stimulant is a single-layered
structure, wherein the single-layered structure has a
pre-determined surface area, thickness, and ADHD stimulant mass
fraction correlating with an immediate release profile of the ADHD
stimulant. In some embodiments, the erodible stimulant material
admixed with an ADHD stimulant is a single-layered structure,
wherein the single-layered structure is embedded in a substrate
material. In some embodiments, the erodible stimulant material
admixed with an ADHD stimulant is a single-layered structure,
wherein the single-layered structure is attached to a portion of an
oral drug dosage form. In some embodiments, the oral drug dosage
form comprises two or more single-layered structures comprising an
erodible stimulant material admixed with an ADHD stimulant.
[0104] In some embodiments, the single-layered structure of an
erodible stimulant material admixed with an ADHD stimulant has a
surface area of at least about 10 mm.sup.2, such as at least about
any of 20 mm.sup.2, 30 mm.sup.2, 40 mm.sup.2, 50 mm.sup.2, 60
mm.sup.2, 70 mm.sup.2, 80 mm.sup.2, 90 mm.sup.2, or 100
mm.sup.2.
[0105] In some embodiments, the single-layered structure of an
erodible stimulant material admixed with an ADHD stimulant has a
thickness of at least about 0.2 mm, such as at least about any of
0.25 mm, 0.5 mm, 0.75 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm,
4 mm, 4.5 mm, or 5 mm. In some embodiments, the erodible stimulant
material admixed with an ADHD stimulant has a thickness of about
0.52 mm.
[0106] In some embodiments, the drug mass faction of a
single-layered structure of an erodible stimulant material admixed
with an ADHD stimulant is at least about 0.0001, such as at least
about any of 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05,
0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45,
or 0.5. In some embodiments, the drug mass faction of a
single-layered structure of an erodible stimulant material admixed
with an ADHD stimulant is about any of 0.0001, 0.0005, 0.001,
0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,
0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5.
[0107] In some embodiments, the oral drug dosage form comprises a
multi-layered structure comprising a plurality of layers of an
erodible stimulant material admixed with an ADHD stimulant. In some
embodiments, erosion of a multi-layered structure comprising a
plurality of layers of an erodible stimulant material admixed with
an ADHD stimulant correlates with the release of the ADHD stimulant
from an oral drug dosage form. In some embodiments, the ADHD
stimulant is released from the oral drug dosage form according to a
sustained release profile. One of ordinary skill in the art will
readily understand that the same concepts regarding multi-layered
structure for configuring and formulating a desired drug release
profile of an ADHD non-stimulant discussed above apply and teach
configuring and formulating a desired drug release profile of an
ADHD stimulant.
[0108] In some embodiments, the multi-layered structure comprising
a plurality of layer of an erodible stimulant material admixed with
an ADHD stimulant is embedded in a substrate material.
[0109] The multi-layered structures comprising an erodible
stimulant material admixed with an ADHD stimulant described herein
may comprise any number of layers. In some embodiments, the
multi-layered structure comprises at least three layers of an
erodible stimulant material admixed with an ADHD stimulant. In some
embodiments, the multi-layered structure comprises 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 layers of an
erodible stimulant material admixed with an ADHD stimulant.
[0110] In some embodiments, each layer of an erodible stimulant
material admixed with an ADHD stimulant of a multi-layered
structure has a pre-determined surface area, thickness, and ADHD
stimulant mass fraction correlating with a sustained release
profile of the ADHD stimulant.
[0111] In some embodiments, the surface areas of two or more layers
of the erodible stimulant material admixed with the ADHD stimulant
of the multi-layered structure are different. In some embodiments,
each successive layer of the erodible stimulant material admixed
with the ADHD stimulant of the multi-layered structure, proceeding
from the top layer to the bottom layer, has a smaller surface area.
In some embodiments, each layer of the erodible stimulant material
admixed with the ADHD stimulant of the multi-layered structure is
concentrically positioned.
[0112] In some embodiments, the surface area of each layer of an
erodible stimulant material admixed with an ADHD stimulant of a
multi-layered structure is between about 1 mm.sup.2 to about 100
mm.sup.2, such as any of about 3 mm.sup.2 to about 26 mm.sup.2, or
about 4.5 mm.sup.2 to about 51 mm.sup.2. In some embodiments, the
surface area of each layer of an erodible stimulant material
admixed with an ADHD stimulant of a multi-layered structure is at
least about 10 mm.sup.2, such as at least about any of 20 mm.sup.2,
30 mm.sup.2, 40 mm.sup.2, 50 mm.sup.2, 60 mm.sup.2, or 70
mm.sup.2.
[0113] In some embodiments, the thickness of a layer can be any
thickness, such as a thickness suitable for production by 3D
printing. In some embodiments, the thicknesses of two or more
layers of an erodible stimulant material admixed with an ADHD
stimulant of a multi-layered structure are different. In some
embodiments, the thicknesses of two or more layers of an erodible
stimulant material admixed with an ADHD stimulant of a
multi-layered structure are the same.
[0114] In some embodiments, the thickness of each layer of an
erodible stimulant material admixed with an ADHD stimulant of a
multi-layered structure is between about 0.05 mm to about 1 mm,
such as between about 0.2 mm to about 0.7 mm. In some embodiments,
the thickness of a layer of an erodible stimulant material admixed
with an ADHD stimulant of a multi-layered structure is less than
about 1.0 mm, such as less than about any of 0.95 mm, 0.9 mm, 0.85
mm, 0.8 mm, 0.75 mm, 0.7 mm, 0.65 mm, 0.6 mm, 0.55 mm, 0.5 mm, 0.45
mm, 0.4 mm, 0.35 mm, 0.3 mm, 0.25 mm, 0.2 mm, 0.15 mm, 0.1 mm, or
0.05 mm. In some embodiments, the thickness of a layer of an
erodible stimulant material admixed with an ADHD stimulant of a
multi-layered structure is greater than about 0.01 mm, such as
greater than about any of 0.05 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.25
mm, 0.3 mm, 0.35 mm, 0.4 mm, 0.45 mm, 0.5 mm, 0.55 mm, 0.6 mm, 0.65
mm, 0.7 mm, 0.75 mm, 0.8 mm, 0.85 mm, 0.9 mm, 0.95 mm, or 1 mm. In
some embodiments, the thickness of a layer of an erodible stimulant
material admixed with an ADHD stimulant of a multi-layered
structure is about any of 0.65 mm, 0.52 mm, or 0.26 mm.
[0115] In some embodiments, the drug mass faction of a layer of an
erodible stimulant material admixed with an ADHD stimulant is at
least about 0.0001, such as at least about any of 0.0005, 0.001,
0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1,
0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5. In some embodiments,
the drug mass faction of a layer of an erodible stimulant material
admixed with an ADHD stimulant is about any of 0.0001, 0.0005,
0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09,
0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5. In some
embodiments, the drug mass fractions of two or more layers of an
erodible stimulant material admixed with an ADHD stimulant of a
multi-layered structure are the same. In some embodiments, the drug
mass fractions of two or more layers of an erodible stimulant
material admixed with an ADHD stimulant of a multi-layered
structure are different.
[0116] In some embodiments, the multi-layered structure comprises a
top layer of a first erodible stimulant material admixed with an
ADHD stimulant and another layer of a second erodible stimulant
material admixed with the ADHD stimulant. In some embodiments, the
multi-layered structure comprises a top layer of a first erodible
stimulant material admixed with an ADHD stimulant and all other
layers of a second erodible stimulant material admixed with the
ADHD stimulant. In some embodiments, the first erodible stimulant
material and the second erodible stimulant material are the same.
In some embodiments, the first erodible stimulant material and the
second erodible stimulant material are different. In some
embodiments, the first erodible stimulant material and the second
erodible stimulant material are different, wherein the erosion rate
of the first erodible stimulant material is slower than the second
erodible stimulant material.
[0117] In some embodiments, the oral dosage form comprises a first
multi-layered structure comprising an erodible non-stimulant
material admixed with an ADHD non-stimulant and a second
multi-layered structure comprising an erodible stimulant material
admixed with an ADHD stimulant. In some embodiments, the first
multi-layered structure and the second multi-layered structure have
the same number of layers. In some embodiments, the first
multi-layered structure and the second multi-layered structure have
the same number of layers, wherein the corresponding layers of each
multi-layered structure have the same layer surface area and
thickness. In some embodiments, the first multi-layered structure
and the second multi-layered structure have the same number of
layers, wherein the corresponding layers of each multi-layered
structure have a different layer surface area and/or layer
thickness. In some embodiments, the first multi-layered structure
and the second multi-layered structure have a different number of
layers.
[0118] One of ordinary skill in the art will readily appreciate
that the teachings of the present disclosure regarding separate
multi-layered structures, namely a multi-layered structure
comprising an erodible non-stimulant material admixed with an ADHD
non-stimulant and a multi-layered structure comprising an erodible
stimulant material admixed with an ADHD stimulant, may be combined
to form any combination of one or more multi-layered structures
configured and formulated for a desired release profile of an ADHD
non-stimulant and a desired release profile of an ADHD stimulant.
In some embodiments, the multi-layered structure comprises an
erodible non-stimulant material admixed with an ADHD non-stimulant
and an erodible stimulant material admixed with an ADHD stimulant.
In some embodiments, the multi-layered structure comprises a first
layer of an erodible non-stimulant material admixed with an ADHD
non-stimulant and a second layer of an erodible stimulant material
admixed with an ADHD stimulant. In some embodiments, the
multi-layered structure comprises an erodible
non-stimulant/stimulant material admixed with an ADHD stimulant and
an ADHD non-stimulant.
i. Immediate Release Profiles
[0119] The oral drug dosage forms described herein provide release
of an ADHD stimulant according to an immediate release profile.
[0120] In some embodiments, the immediate release profile is
release of substantially all of an ADHD stimulant of an oral drug
dosage form within about 60 minutes of administration, such as
within about any of 55 minutes, 50 minutes, 45 minutes, 40 minutes,
35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10
minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4
minutes, 3 minutes, 2 minutes, or 1 minute of administration.
[0121] In some embodiments, the immediate release profile is
release of at least about 85% of an ADHD stimulant of an oral drug
dosage form, such as release of at least about any of 87.5%, 90%,
92.5%, 95%, 97.5%, or 100%, in less than about 15 minutes, such as
less than about any of 14 minutes, 13 minutes, 12 minutes, 11
minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5
minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute.
[0122] In some embodiments, the immediate release profile is a
burst release profile. In some embodiments, the immediate release
profile is a bolus release profile.
ii. Sustained Release Profiles
[0123] The oral drug dosage forms described herein provide release
of an ADHD stimulant according to a sustained release profile.
[0124] In some embodiments, the oral drug dosage forms described
herein provide controlled (e.g., desired) release of an ADHD
stimulant over at least about 4 hours, such as at least about any
of 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,
12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18
hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24
hours. In some embodiments, the oral drug dosage forms described
herein provide controlled (e.g., desired) release of an ADHD
stimulant over about any of 4 hours, 5 hours, 6 hours, 7 hours, 8
hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours,
15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21
hours, 22 hours, 23 hours, or 24 hours.
[0125] In some embodiments, the sustained release profile comprises
a zero-order release profile, a first-order release profile, a
delayed release profile, a pulsed release profile, an iterative
pulsed release profile, or a combination thereof.
[0126] In some embodiments, the sustained release profile is
similar, e.g., equivalent or bioequivalent, to a desired drug
release profile or a release profile of a reference oral drug
dosage form. In some embodiments, the desired drug release profile,
e.g., sustained release profile, of an oral drug dosage form is
similar, e.g., equivalent or bioequivalent, to the in vitro
dissolution rate of the oral drug dosage form. In some embodiments,
the desired drug release profile of an oral drug dosage form is
similar, e.g., equivalent or bioequivalent, to the in vivo drug
release profile of the oral drug dosage form. In some embodiments,
the in vivo drug release profile of an oral drug dosage form is
based on evaluation of the in vitro dissolution rate of the oral
drug dosage form. In some embodiments, the desired drug release
profile of an oral drug dosage form is similar, e.g., equivalent or
bioequivalent, to the release profile of a reference oral drug
dosage form.
[0127] In some embodiments, the dissolution similarity is evaluated
using the similarity factor. In some embodiments, the dissolution
similarity is evaluated using Chow's method.
[0128] In some embodiments, the release of the ADHD stimulant is
measured at one or more of about pH 2, about pH 7.0, and about pH
4.5.
iii. ADHD Stimulants
[0129] The oral drug dosage forms described herein comprise an
erodible stimulant material admixed with an ADHD stimulant. ADHD
stimulants act by, e.g., (i) inhibiting reuptake of norepinephrine
and dopamine into presynaptic neurons (e.g., methylphenidates such
as methylphenidate (d,l) and dexmethylphenidate); and (ii)
promoting release of dopamine and norepinephrine from presynaptic
neurons and inhibiting reuptake (e.g., amphetamines such as mixed
amphetamine salts, dextroamphentamine, and lisdexamfetamine
(prodrug)).
[0130] In some embodiments, the ADHD stimulant is a neuromodulator.
In some embodiments, the ADHD stimulant is an agent that increases
the levels of dopamine in an individual. In some embodiments, the
ADHD stimulant is an agent that increases the levels of
norepinephrine in an individual. In some embodiments, the ADHD
stimulant is a norepinephrine-dopamine reuptake inhibitor. In some
embodiments, the ADHD stimulant is a dopamine transporter
inhibitor. In some embodiments, the ADHD stimulant is a
norepinephrine transporter inhibitor. In some embodiments, the ADHD
stimulant is a serotonin transporter inhibitor.
[0131] In some embodiments, the ADHD stimulant is an amphetamine, a
methylphenidate, pharmaceutically acceptable salts thereof, or a
combination thereof. In some embodiments, the ADHD stimulant is an
amphetamine. In some embodiments, the ADHD stimulant is a
methylphenidate.
[0132] In some embodiments, the amphetamine is amphetamine or
methamphetamine. Amphetamines include, but are not limited to,
levoamphetamine, levamfetamine, dextroamphetamine, dexamfetamine,
lisdexamfetamine, .alpha.-methylphenethylamine, D-amphetamine,
(5)-amphetamine, (+)-amphetamine, (R)-amphetamine, (-)-amphetmaine,
or L-amphetmaine, and pharmaceutically acceptable salts thereof,
including for example, dextroamphetamine aspartate monohydrate,
dextroamphetamine sulfate, amphetamine sulfate, mixed salt
amphetamines, and dextroamphetamine saccharate, or a combination
thereof.
[0133] In some embodiments, the methamphetamine is methamphetamine,
metamfetamine, or pharmaceutically acceptable salts thereof,
including methamphetamine hydrochloride. Methylphenidates include,
but are not limited to, N-methylamphetamine,
N,.alpha.-dimethylphenethylamine, and desoxyephedrine.
[0134] In some embodiments, the methylphenidate is methylphenidate,
dextromethylphenidate (dexmethylphenidate), methyl phenidyacetate,
a pharmaceutically acceptable salt thereof, including
methylphenidate HCl, dexmethylphenidate HCl, or a combination
thereof.
[0135] In some embodiments, the amount of an ADHD stimulant in an
oral drug dosage form is about 1 mg to about 60 mg, such as any of
about 1.75 mg to about 60 mg, about 1.75 mg to about 20 mg, or
about 2.5 mg to about 50 mg. In some embodiments, the amount of an
ADHD stimulant in an oral drug dosage form is less than about 60
mg, such as less than about any of 55 mg, 50 mg, 45 mg, 40 mg, 35
mg, 30 mg, 25 mg, 20 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg,
9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4.5 mg, 4 mg, 3.5 mg, 3 mg, 2.5 mg, 2
mg, 1.75 mg, or 1.5 mg. In some embodiments, the amount of an ADHD
stimulant in an oral drug dosage form is greater than about 1 mg,
such as greater than about any of 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3
mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11
mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,
45 mg, 50 mg, 55 mg, or 60 mg. In some embodiments, the amount of
an ADHD stimulant in an oral drug dosage form is about any of 1 mg,
1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6
mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20
mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg.
[0136] In some embodiments, the amount of an ADHD stimulant in an
oral drug dosage form is a sub-therapeutic dose when the ADHD
stimulant is not administered in conjunction with an ADHD
non-stimulant.
[0137] In some embodiments, the ADHD stimulant of an oral drug
dosage form is a methylphenidate or a pharmaceutically acceptable
salt thereof, wherein the amount of the methylphenidate or the
pharmaceutically acceptable salt thereof in the oral drug dosage
form is between about 1.75 mg to about 60 mg. In some embodiments,
the ADHD stimulant of an oral drug dosage form is a methylphenidate
or a pharmaceutically acceptable salt thereof, wherein the amount
of the methylphenidate or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is about any of 1.75 mg, 2 mg,
2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25
mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg.
[0138] In some embodiments, the ADHD stimulant of an oral drug
dosage form is dextromethylphenidate (dexmethylphenidate) or a
pharmaceutically acceptable salt thereof, wherein the amount of
dextromethylphenidate or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is between about 1.75 mg to
about 20 mg. In some embodiments, the ADHD stimulant of an oral
drug dosage form is dextromethylphenidate (dexmethylphenidate) or a
pharmaceutically acceptable salt thereof, wherein the amount of the
dextromethylphenidate or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is about any of 1.75 mg, 2 mg,
2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, or 20
mg.
[0139] In some embodiments, the ADHD stimulant of an oral drug
dosage form is dextroamphetamine or a pharmaceutically acceptable
salt thereof, wherein the amount of dextroamphetamine or the
pharmaceutically acceptable salt thereof in the oral drug dosage
form is between about 2.5 mg to about 50 mg. In some embodiments,
the ADHD stimulant of an oral drug dosage form is dextroamphetamine
or a pharmaceutically acceptable salt thereof, wherein the amount
of dextroamphetamine or the pharmaceutically acceptable salt
thereof in the oral drug dosage form is about any of 2.5 mg, 3 mg,
3.5 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35
mg, 40 mg, 45 mg, or 50 mg.
[0140] Those of ordinary skill in the art will recognize that the
provided list of ADHD stimulants and dosages is not limiting and
recognize additional ADHD stimulant pharmaceuticals and dosages
which will be useful with embodiments of the present
disclosure.
D. Substrate Materials
[0141] The oral drug dosage form described herein comprise an
erodible non-stimulant material admixed with an ADHD non-stimulant
embedded in a substrate material.
[0142] In some embodiments, the substrate material is an insulating
material that is impermeable to gastrointestinal fluid, wherein the
insulating material forms a barrier between the gastrointestinal
fluid and a portion of an erodible non-stimulant material admixed
with an ADHD non-stimulant. In some embodiments, the substrate
material is an insulating material that is impermeable to
gastrointestinal fluid, wherein the insulating material forms a
barrier between the gastrointestinal fluid and a portion of a
multi-layered structure comprising a plurality of layers of an
erodible non-stimulant material admixed with an ADHD
non-stimulant.
[0143] In some embodiments, the substrate material, such as an
insulating material, is an erodible material. In some embodiments,
the insulating material is an erodible material. In some
embodiments, the substrate material has a slower erosion rate than
an erodible non-stimulant material admixed with an ADHD
non-stimulant. In some embodiments, the substrate material erodes
at a specified pH, such as at a pH of greater than about any of 3,
3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7.
[0144] In some embodiments, the barrier formed by a substrate
material around an erodible non-stimulant material admixed with an
ADHD non-stimulant has a uniform thickness. In some embodiments,
the barrier formed by a substrate material around an erodible
non-stimulant material admixed with an ADHD non-stimulant has a
varied thickness. In some embodiments, the barrier formed by a
substrate material is at least about 0.01 mm, such as at least
about any of 0.05 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm, 0.3 mm,
0.35 mm, 0.4 mm, 0.45 mm, 0.5 mm, 0.55 mm, 0.6 mm, 0.65 mm, 0.7 mm,
0.75 mm, 0.8 mm, 0.85 mm, 0.9 mm, 0.95 mm, or 1 mm.
[0145] In some embodiments, the oral drug dosage forms described
herein further comprise a layer of a substrate material that forms
a substrate rim, wherein the substrate rim forms a space, and
wherein the space is on top of a multi-layered structure. For
example, as shown in FIG. 2A, the exemplary oral drug dosage form
200 comprises a substrate material that forms a rim 205 above the
top of a multi-layered structure comprising a plurality of layers
of an erodible non-stimulant material admixed with an ADHD
non-stimulant 210. The rim form the space 215 shown in FIG. 2A. In
some embodiments, the substrate rim is at least about 0.01 mm (as
measured from the top of a multi-layered structure of an erodible
non-stimulant material admixed with an ADHD non-stimulant), such as
at least about any of 0.05 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm,
0.3 mm, 0.35 mm, 0.4 mm, 0.45 mm, 0.5 mm, 0.55 mm, 0.6 mm, 0.65 mm,
0.7 mm, 0.75 mm, 0.8 mm, 0.85 mm, 0.9 mm, 0.95 mm, or 1 mm.
[0146] In some embodiments, the space is not filled with a
material. In some embodiments, the space is filled with an erodible
material. In some embodiments, the space is filled with an erodible
material admixed with a drug, such as an ADHD stimulant.
E. Erodible Materials of the Oral Drug Dosage Forms
[0147] The erodible material described herein, such as an erodible
non-stimulant material, an erodible stimulant material, erodible
intermediate material, or a substrate material, may comprise a
thermoplastic material.
[0148] In some embodiments, the thermoplastic material is edible
(i.e., suitable for consumption by an individual). In some
embodiments, the thermoplastic material is selected from the group
consisting of a hydrophilic polymer, a hydrophobic polymer, a
swellable polymer, a non-swellable polymer, a porous polymer, a
non-porous polymer, an erodible polymer (such as a dissolvable
polymer), a pH sensitive polymer, a natural polymer (such as
shellac), a wax-like material, and a combination thereof. In some
embodiments, the thermoplastic material is selected from the group
consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol graft copolymer 57/30/13,
polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA),
polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40,
polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and
polyvinylpyrrolidone (PVP) 80/20, vinylpyrrolidone-vinyl acetate
copolymer (VA64), polyethylene glycol-polyvinyl alcohol graft
copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinyl
alcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), an (optionally
alkyl-, methyl-, or ethyl-) acrylate, a methacrylate copolymer, an
ethacrylate copolymer, poly(butyl
methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl
methacrylate) 1:2:1,
poly(dimethylaminoethylmethacrylate-co-methacrylic esters),
poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride), poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) 7:3:1, poly(methacrylic
acid-co-methylmethacrylate) 1:2, poly(methacylic acid-co-ethyl
acrylate) 1:1, poly(methacylic acid-co-methyl methacrylate) 1:1,
poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),
hyperbranched polyesteramide, a cellulose or cellulose derivative,
hydroxypropyl methylcellulose phthalate, hypromellose phthalate,
hydroxypropyl methylcellulose or hypromellose (HMPC), hydroxypropyl
methylcellulose acetate succinate or hypromellose acetate succinate
(HPMCAS), poly(lactide-co-glycolide) (PLGA), carbomer,
poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer,
polyethylene (PE), and polycaprolactone (PCL), hydroxyl propyl
cellulose (HPC), polyoxyl 40 hydrogenerated castor oil, methyl
cellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropyl
methylcellulose phthalate (HPMCP), poloxamer, hydrogenated castor
and soybean oil, glyceryl palmitostearate, carnauba wax, polylactic
acid (PLA), polyglycolic acid (PGA), cellulose acetate butyrate
(CAB), colloidal silicon dioxide, a saccharide, glucose, polyvinyl
acetate phthalate (PVAP), a wax, beeswax, hydrogel, gelatin,
hydrogenated vegetable oil, polyvinyl acetal diethyl aminolactate
(AEA), paraffin, shellac, sodium alginate, cellulose acetate
phthalate (CAP), fatty oil, arabic gum, xanthan gum, glyceryl
monostearate, octadecanoic acid, and a combination thereof.
[0149] In some embodiments, the erodible material comprises a
non-thermoplastic material. In some embodiments, the erodible
material is a non-thermoplastic material. In some embodiments, the
non-thermoplastic material is selected from the group consisting of
starch, pregelatinized starch, sodium starch glycolate (CMS-Na),
sucrose, dextrin, lactose, microcrystalline cellulose (MCC),
mannitol, magnesium stearate (MS), powdered silica gel, sodium
alginate, titanium dioxide, glycerin, syrup, lecithin, soybean oil,
tea oil, ethanol, propylene glycol, glycerol, Tween, animal fats,
silicone oils, cacao butter, fatty acid glycerides, vaseline,
chitosan, cetyl alcohol, stearyl alcohol, and a combination
thereof.
[0150] In some embodiments, the substrate material, e.g.,
insulating material, is selected from the group consisting of
cellulose ethers, cellulose esters and acrylic resins. In some
embodiments, the insulating material is selected from the group
consisting of ethylcellulose, hydroxypropylmethylcellulose,
hydroxypropyl cellulose, hydroxymethylcellulose, poly(meth)acrylic
acid and derivatives thereof, such as the salts, amides or esters
thereof are suitable for use as thermoplastic materials. In some
embodiments, the insulating material is selected from the group
consisting of mono- or diglycerides of C12-C30 fatty acids, C12-C30
fatty alcohols, waxes, and a combination thereof.
[0151] In some embodiments, the thermoplastic material is admixed
with another agent, such as an excipient and/or a plasticizer. In
some embodiments, the thermoplastic material is admixed with an
excipient. In some embodiments, the excipient is selected from the
group consisting of cocoa butter, polyethylene glycol (PEG),
sucrose, glucose, galactose, fructose, xyloselactose, maltose,
trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose,
fructo-oligosaccharides, and a combination thereof. In some
embodiments, the thermoplastic material is admixed with a
plasticizer. In some embodiments, the plasticizer is triethyl
citrate (TEC). In some embodiments, the plasticizer is selected
from the group consisting of block copolymers of
polyoxyethylene-polyoxypropylene, vitamin e polyethylene glycol
succinate, hydroxystearate, polyethylene glycol (such as PEG400),
macrogol cetostearyl ether 12, polyoxyl 20 cetostearyl ether,
polysorbate 20, polysorbate 60, polysorbate 80, acetin, acetylated
triethyl citrate, tributyl citrate, tributyl o-acetylcitrate,
triethyl citrate, polyoxyl 15 hydroxystearate, peg-40 hydrogenated
castor oil, polyoxyl 35 castor oil, dibutyl sebacate,
diethylphthalate, glycerine, methyl 4-hydroxybenzoate, glycerol,
castor oil, oleic acid, tryacetin, polyalkylene glycol, and a
combination thereof.
F. Abuse Deterrence
[0152] In some embodiments, the oral drug dosage forms provided
herein are configured and formulated to provide an abuse-deterrent
characteristic. In some embodiments, the present disclosure
provides oral drug dosage forms which deter individuals from taking
unadvisable, off-prescription, off-label, unadvisable
administration routes (e.g., intravenously, snorting, etc.), and/or
unintended dosages of the drug dosage forms described herein. In
some embodiments, the material of the substrate material and/or the
erodible stimulant material admixed with an ADHD stimulant is
selected based on a property of the material, e.g., crushability.
In some embodiments, the oral drug dosage form further comprises an
agent to deter abuse of the drug dosage form. In some embodiments,
the agent to deter abuse of a drug dosage form is a nasal irritant,
a mucosal irritant, a polymer composition, a surfactant, or an
emetic composition. Other suitable compositions are known in the
art (see, e.g., Handbook of Pharmaceutical Excipients, 4th Ed.
(2003), which is hereby incorporated by references in its
entirety). In some embodiments, the stimulant composition comprises
an abuse deterrent. In some embodiments, the oral drug dosage form
further comprises an ADHD stimulant antagonist or a non-sequestered
aversive excipient.
[0153] In some embodiments, the erodible material, such as an
erodible non-stimulant material, an erodible stimulant material,
erodible intermediate material, or a substrate material, is
selected based on a property of the material that is useful for
abuse deterrence. In some embodiments, the oral drug dosage form,
or component thereof, is produced using a hot melt extrusion
technique. In some embodiments, the oral drug dosage form, or
component thereof, is produced using a hot melt extrusion
technique, wherein the hot melt extrusion technique comprises using
high-molecular weight polyethylene oxide (PEO) co-melted with an
ADHD stimulant.
G. Exemplary Oral Drug Dosage Forms
[0154] In some embodiments, the oral drug dosage form comprises:
(a) a multi-layered structure comprising a plurality of layers of
an erodible non-stimulant material admixed with an ADHD
non-stimulant; and (b) an erodible stimulant material admixed with
an ADHD stimulant, wherein the erodible non-stimulant material
admixed with the ADHD non-stimulant is embedded in a substrate
material, and wherein upon exposure to gastrointestinal fluid the
ADHD non-stimulant is released according to a sustained release
profile and the ADHD stimulant is released according to an
immediate release profile. In some embodiments, the multi-layered
structure comprises four layers of an erodible non-stimulant
material admixed with and ADHD non-stimulant. In some embodiments,
the sustained release profile comprises a zero-order release
profile. In some embodiments, the sustained release profile is ADHD
non-stimulant release over about 12 hour. In some embodiments, the
ADHD non-stimulant is one or more of clonidine guanfacine,
atomoxetine, or a prodrug thereof. In some embodiments, the
immediate release profile is ADHD stimulant release of at least
about 85% of the ADHD stimulant in the oral drug dosage form within
15 minutes after oral administration. In some embodiments, the ADHD
stimulant is one or more of methylphenidate (d,l),
dexmethylphenidate, mixed amphetamine salts, dextroamphetamine,
lisdexamfetamine, or a prodrug thereof.
[0155] In some embodiments, the oral drug dosage form comprises:
(a) a first multi-layered structure comprising a plurality of
layers of an erodible non-stimulant material admixed with an ADHD
non-stimulant; and (b) a second multi-layered structure comprising
a plurality of layers of an erodible stimulant material admixed
with an ADHD stimulant, wherein the erodible non-stimulant material
admixed with the ADHD non-stimulant is embedded in a substrate
material, and wherein upon exposure to gastrointestinal fluid the
ADHD non-stimulant is released according to a sustained release
profile. In some embodiments, the ADHD stimulant is released
according to a sustained release profile. In some embodiments, the
first multi-layered structure comprises four layers of an erodible
non-stimulant material admixed with and ADHD non-stimulant. In some
embodiments, the sustained release profile comprises a zero-order
release profile. In some embodiments, the sustained release profile
is ADHD non-stimulant release over about 12 hour. In some
embodiments, the ADHD non-stimulant is one or more of clonidine
guanfacine, atomoxetine, or a prodrug thereof. In some embodiments,
the ADHD stimulant is one or more of methylphenidate (d,l),
dexmethylphenidate, mixed amphetamine salts, dextroamphetamine,
lisdexamfetamine, or a prodrug thereof.
[0156] In some embodiments, the oral drug dosage form comprises:
(a) a first multi-layered structure comprising a plurality of
layers of an erodible non-stimulant material admixed with an ADHD
non-stimulant; (b) a second multi-layered structure comprising a
plurality of layers of a first erodible stimulant material admixed
with an ADHD stimulant; and (c) an second erodible stimulant
material admixed with the ADHD stimulant, wherein the erodible
non-stimulant material admixed with the ADHD non-stimulant is
embedded in a substrate material, and wherein upon exposure to
gastrointestinal fluid the ADHD non-stimulant is released according
to a sustained release profile, the ADHD stimulant is released from
the first erodible stimulant material according to a sustained
release profile, and the ADHD stimulant is released from the third
erodible stimulant material according to an immediate release
profile.
[0157] In some embodiments, the first multi-layered structure
comprises four layers of an erodible non-stimulant material admixed
with and ADHD non-stimulant. In some embodiments, the sustained
release profile of the ADHD non-stimulant comprises a zero-order
release profile. In some embodiments, the sustained release profile
of the ADHD non-stimulant is ADHD non-stimulant release over about
12 hour. In some embodiments, the ADHD non-stimulant is one or more
of clonidine guanfacine, atomoxetine, or a prodrug thereof. In some
embodiments, the immediate release profile is ADHD stimulant
release of at least about 85% of the ADHD stimulant in the oral
drug dosage form within 15 minutes after oral administration. In
some embodiments, the second erodible stimulant material admixed
with the ADHD stimulant is a layer on top of the top layer of the
second multi-layered structure. In some embodiments, the ADHD
stimulant is one or more of methylphenidate (d,l),
dexmethylphenidate, mixed amphetamine salts, dextroamphetamine,
lisdexamfetamine, or a prodrug thereof.
Methods of Designing
[0158] The present disclosure provides methods of designing oral
drug dosage forms comprising: (a) an erodible non-stimulant
material admixed with an ADHD non-stimulant; and (b) an erodible
stimulant material admixed with an ADHD stimulant, wherein the
erodible non-stimulant material admixed with the ADHD non-stimulant
is embedded in a substrate material, and wherein upon exposure to
gastrointestinal fluid the ADHD non-stimulant is released according
to a sustained release profile and the ADHD stimulant is released
according to an immediate release profile.
[0159] In some embodiments, the method of designing an oral drug
dosage form to provide a sustained release profile of an ADHD
non-stimulant and an immediate release profile of an ADHD stimulant
comprises: (a) obtaining the sustained release profile of the ADHD
non-stimulant; (b) selecting an erodible non-stimulant medium; (c)
obtaining an erosion rate of the non-stimulant medium; and (d)
determining the thickness, surface area, and/or ADHD non-stimulant
drug mass fraction correlating with the sustained release profile.
In some embodiments, the method of designing an oral drug dosage
form to provide a sustained release profile of an ADHD
non-stimulant and an immediate release profile of an ADHD stimulant
further comprises: (e) selecting an erodible stimulant medium; (f)
obtaining the total weight of the stimulant medium admixed with the
ADHD stimulant; (g) obtaining the density of the stimulant medium
admixed with the ADHD stimulant; and (h) obtaining the volume of
the stimulant medium admixed with the ADHD stimulant; and (i)
determining a shape, with the volume from step (h), of the
stimulant medium admixed with the ADHD stimulant. In some
embodiments, the method of designing an oral drug dosage form
described herein comprises selecting a substrate material. In some
embodiments, the method of designing an oral drug dosage form
described herein comprises selecting a thickness of a substrate
rim.
[0160] In some embodiments, the methods of designing an oral drug
dosage form described herein may be performed, in whole or in part,
on a computer system. In some embodiments, the computer system
comprises a user interface. In some embodiments, the method
comprises inputting one or more parameters of the oral drug dosage
form into the computer system. In some embodiments, the computer
system is used to calculate the parameters of the oral drug dosage
form to provide a desired drug release profile. In some
embodiments, the computer system comprises three-dimensional
drawing software. In some embodiments, the computer system is used
to create a three-dimensional drawing of an oral drug dosage form
based on the pre-determined parameters of the oral drug dosage
form. In some embodiments, the computer system comprises slicing
software. In some embodiments, the computer system is used to
convert a three-dimensional drawing of an oral drug dosage form
into three-dimensional printing code, e.g., G code. In some
embodiments, the computer system executes the three-dimensional
printing code, thereby printing an oral drug dosage form.
[0161] In some embodiments, the method of designing an oral drug
dosage form described herein comprises adjusting the pre-determine
parameters of a layer comprising an erodible material admixed with
a drug, e.g., an erodible non-stimulant material admixed with an
AMID non-stimulant, the parameters including surface area,
thickness, drug mass fraction, to create new parameters for the
layer, wherein an equal amount of the drug is released from the
prior layer parameters and the adjusted layer parameters over the
erosion time of the layers. In some embodiments, the layer is a
layer of a multi-layered structure of an oral drug dosage form
described herein. In some embodiments, the layer is the top layer
of a multi-layered structure of an oral drug dosage form described
herein.
[0162] In some embodiments, the volume of the layer is adjusted. In
some embodiments, the volume of the layer is increased. In some
embodiments, the top layer of a multi-layered structure is
increased in volume. In some embodiments, the relative amount of a
drug, e.g., per amount of material in the adjusted layer is less
than in the layer prior to adjustment. In some embodiments, the
original layer parameters are adjusted to increase the thickness of
the original layer, wherein the relative amount of the drug in the
layer (e.g., the layer includes the erodible non-stimulant material
and the substrate material) after adjustment is decreased as
compared to the layer prior to adjustment. In some embodiments, the
original layer parameters are adjusted to increase the volume of
the substrate material of the layer.
[0163] In some embodiments, the layer comprising an erodible
material admixed with a drug is adjusted by adding one or more
intermediate layers comprising an erodible intermediate material
not admixed with the drug. In some embodiments, the intermediate
layer comprising an erodible intermediate material not admixed with
the drug is added above the top layer comprising an erodible
non-stimulant material admixed with an ADHD non-stimulant of a
multi-layered structure. In some embodiments, the intermediate
layer comprising an erodible intermediate material not admixed with
the drug is directly below the top layer comprising an erodible
non-stimulant material admixed with an ADHD non-stimulant of a
multi-layered structure.
[0164] In some embodiments, the layer comprising an erodible
material admixed with a drug is adjusted by selecting a substitute
erodible material, wherein the parameters of the layer are adjusted
according to the erosion rate of the substitute erodible material.
In some embodiments, the substitute erodible material admixed with
an ADHD non-stimulant has a slower erosion rate than the erodible
non-stimulant material admixed with an ADHD non-stimulant. In some
embodiments, the substitute erodible material admixed with an ADHD
non-stimulant has a faster erosion rate than the erodible
non-stimulant material admixed with an ADHD non-stimulant. In some
embodiments, the top layer comprising an erodible non-stimulant
material admixed with an ADHD non-stimulant of a multi-layered
structure is adjusted by selecting a substitute erodible material
to admixed with the ADHD non-stimulant. In some embodiments, the
top layer comprising an erodible non-stimulant material admixed
with an ADHD non-stimulant of a multi-layered structure is adjusted
by selecting a substitute erodible material to admixed with the
ADHD non-stimulant, wherein the substitute erodible material has a
slower erosion rate than the erodible non-stimulant material. In
some embodiments, the top layer comprising an erodible
non-stimulant material admixed with an ADHD non-stimulant of a
multi-layered structure is adjusted by selecting a substitute
erodible material to admixed with an ADHD non-stimulant, wherein
the substitute erodible material admixed with the ADHD
non-stimulant has a faster erosion rate than the erodible
non-stimulant material admixed with the ADHD non-stimulant.
[0165] It will be understood by those skilled in the art that the
methods provided herein also encompass methods of printing and
designing based on one or more of the adjusted parameters discussed
herein.
Methods of Three-Dimensional Printing an Oral Drug Dosage Form
[0166] The present disclosure provides methods of three-dimensional
printing an oral drug dosage form described herein. In some
embodiments, the method of three-dimensional printing an oral drug
dosage form formulated and configured to provide a sustained
release profile of an ADHD non-stimulant and an immediate release
profile of an ADHD stimulant comprises: (a) dispensing an erodible
non-stimulant material admixed with an ADHD non-stimulant; (b)
dispensing an erodible stimulant material admixed with an ADHD
stimulant; and (c) dispensing a substrate material, wherein the
erodible non-stimulant material admixed with the ADHD non-stimulant
correlates with the sustained release profile and the erodible
stimulant material admixed with the ADHD stimulant correlates with
the immediate release profile. In some embodiments, the erodible
non-stimulant material admixed with the ADHD non-stimulant forms a
multi-layered structure comprising a plurality of layers of the
erodible non-stimulant material admixed with the ADHD
non-stimulant. In some embodiments, the multi-layered structure is
dispensed according to pre-determined surface areas, thicknesses,
and/or drug mass fractions of each layer of the multi-layered
structure.
[0167] As used herein, "printing," "three-dimensional printing,"
"3D printing," "additive manufacturing," or equivalents thereof,
refers to a process that produces three-dimensional objects, such
as drug dosage forms, layer-by-layer using digital designs. The
basic process of three-dimensional printing has been described in
U.S. Pat. Nos. 5,204,055; 5,260,009; 5,340,656; 5,387,380;
5,503,785; and 5,633,021. Additional U.S. patents and patent
applications that related to three-dimensional printing include:
U.S. Pat. Nos. 5,490,962; 5,518,690; 5,869,170; 6,530,958;
6,280,771; 6,514,518; 6,471,992; 8,828,411; U.S. Publication Nos.
2002/0015728; 2002/0106412; 2003/0143268; 2003/0198677;
2004/0005360. The content of the above U.S. patents and patent
applications is hereby incorporated by reference in their
entirety.
[0168] In some embodiments, an additive manufacturing technique is
used to produce an oral drug dosage forms described herein. In some
embodiments, a layer-by-layer technique is used to produce an oral
drug dosage forms described herein.
[0169] Different 3D printing methods have been developed for drug
dosage form manufacturing in terms of raw materials, equipment, and
solidification. These 3D printing methods include binder deposition
(see Gibson et al., Additive Manufacturing Technologies: 3D
Printing, Rapid Prototyping, and Direct Digital Manufacturing., 2
ed. Springer, New York, 2015; Katstra et al., Oral dosage forms
fabricated by three dimensional printing, J Control Release, 66,
2000; Katstra et al., Fabrication of complex oral delivery forms by
three dimensional printing, Dissertation in Materials Science and
Engineering, Massachusetts Institute of Technology, 2001; Lipson et
al., Fabricated: The New World of 3D printing, John Wiley &
Sons, Inc., 2013; Jonathan, Karim 3D printing in pharmaceutics: a
new tool for designing customized drug delivery systems, Int J
Pharm, 499, 2016), material jetting (see Jonathan, Karim, 3D
printing in pharmaceutics: a new tool for designing customized drug
delivery systems, Int J Pharm, 499, 2016), extrusion (see Gibson et
al., Additive Manufacturing Technologies: 3D Printing, Rapid
Prototyping, and Direct Digital Manufacturing. 2 ed. Springer, New
York, 2015), and photopolymerization (see Melchels et al., A review
on stereolithography and its application in biomedical engineering.
Biomaterials, 31, 2010).
[0170] In some embodiments, the drug dosage forms disclosed herein
are 3D printed using an extrusion method. In some embodiments, the
method of 3D printing comprises using a double screw extrusion
method. In an extrusion process, material is extruded from
robotically-actuated printing heads through printing nozzles.
Unlike binder deposition, which requires a powder bed, extrusion
methods can print on any substrate. A variety of materials can be
extruded for three-dimensional printing, including thermoplastic
materials disclosed herein, pastes and colloidal suspensions,
silicones, and other semisolids. One common type of extrusion
printing is fused deposition modeling, which uses solid polymeric
filaments for printing. In fused deposition modeling, a gear system
drives the filament into a heated nozzle assembly for extrusion
(see Gibson et al., Additive Manufacturing Technologies: 3D
Printing, Rapid Prototyping, and Direct Digital Manufacturing, 2
ed. Springer, New York, 2015).
[0171] In some embodiments, the 3D printing methods disclosed
herein comprise a continuous feed method.
[0172] In some embodiments, the 3D printing methods disclosed
herein comprise a batch feed method.
[0173] The method instructions for 3D printing an oral drug dosage
form disclosed herein may be generated a variety of ways, including
direct coding, derivation from a solid CAD model, or other means
specific to the 3D printing machine's computer interface and
application software. These instructions may include information on
the number and spatial placement of droplets, and on general 3D
print parameters such as the drop spacing in each linear dimension
(X, Y, Z), and volume or mass of fluid per droplet. For a given set
of materials, these parameters may be adjusted in order to refine
the quality of structure created. The overall resolution of the
structure created is a function of the powder particle size, the
fluid droplet size, the print parameters, and the material
properties.
[0174] Because 3D printing may handle a range of pharmaceutical
materials and control both composition and architecture locally, 3D
printing is well suited to the fabrication of drug dosage forms
with complex geometry and composition in accordance with the
present invention.
[0175] Manufacturing the drug dosage forms using 3D printing
methods also facilitates personalized medicine. Personalized
medicine refers to stratification of patient populations based on
biomarkers to aid therapeutic decisions and personalized dosage
form design. Modifying digital designs is easier than modifying
physical equipment. Also, automated, small-scale three-dimensional
printing may have negligible operating cost. Hence, 3D printing can
make multiple small, individualized batches economically feasible
and enable personalized dosage forms designed to improve
adherence.
[0176] Personalized drug dosage forms allow for tailoring the
amount of drug delivered based on a patient's mass and metabolism.
3D printed dosage forms could ensure accurate dosing in growing
children and permit personalized dosing of highly potent drugs.
Personalized dosage forms can also combine all of patients'
medications into a single daily dose, thus improve patients'
adherence to medication and treatment compliance.
[0177] In some embodiments, the methods for 3D printing of an oral
drug dosage form described herein further comprise dispensing an
insulating material that is impermeable to gastrointestinal fluid,
wherein the insulating material forms a barrier between the
gastrointestinal fluid and a portion of a multi-layered
structure.
[0178] In some embodiments, the methods for 3D printing of an oral
drug dosage form described herein further comprise dispensing an
erodible intermediate material not admixed with the drug. In some
embodiments, the erodible intermediate material is the same as an
erodible non-stimulant material admixed with an ADHD non-stimulant.
In some embodiments, the erodible intermediate material is
different than an erodible non-stimulant material admixed with an
ADHD non-stimulant.
[0179] In some embodiments, the erodible non-stimulant material
admixed with the ADHD non-stimulant and the erodible stimulant
material admixed with the ADHD stimulant are dispensed by different
printing heads.
[0180] In some embodiments, the erodible non-stimulant material
admixed with the ADHD non-stimulant, the erodible stimulant
material admixed with the ADHD stimulant, and the substrate
material are dispensed by different printing heads.
[0181] In some embodiments, the erodible non-stimulant material
admixed with the ADHD non-stimulant, the erodible stimulant
material admixed with the ADHD stimulant, the substrate material,
and the erodible intermediate material are dispensed by different
printing heads.
[0182] In some embodiments, the 3D printing is carried out by fused
deposition modeling (FDM). In some embodiments, the 3D printing is
carried out by non-filament FDM. In some embodiments, the FDM is a
filament FDM. In some embodiments, the 3D printing is carried out
by hot melt extrusion coupled with a three-dimensional printing
technique, such as FDM. In some embodiments, the 3D printing is
carried out by inkjet printing. In some embodiments, the 3D
printing is carried out by selective laser sintering (SLS). In some
embodiments, the 3D printing is carried out by stereolithography
(SLA or SL). In some embodiments, the 3D printing is carried out by
PolyJet, Multi-Jet Printing System (MJP), Perfactory, Solid Object
Ultraviolet-Laser Printer, Bioplotter, 3D Bioprinting, Rapid Freeze
Prototyping, Fused Deposition Modelling (FDM), Benchtop System,
Selective Deposition Lamination (SDL), Laminated Objet
Manufacutring (LOM), Ultrasonic Consolidation, ColorJet Printing
(CJP), EOSINT Systems, Laser Engineered Net Shaping (LENS) and
Aerosol Jet System, Electron Beam Melting (EBM), Laser CUSING.RTM.,
Selective Laser Melting (SLM), Phenix PXTM Series, Microsintering,
Digital Part Materialization (DPM), or VX System.
[0183] The 3D printing methods of the present disclosure encompass
printing the materials in any order that will allow for production
of an oral drug dosage form disclosed herein. In some embodiments,
the method for three-dimensional printing of a drug dosage form
comprises dispensing a substrate material to form a structure of a
specific thickness, wherein a multi-layered structure is dispensed
into the structure of the substrate material. In some embodiments,
the method for three-dimensional printing of an oral drug dosage
form further comprises dispensing the substrate material to form a
structure of a specific thickness on top of a previously dispensed
structure of the substrate material.
[0184] In some embodiments, the method for three-dimensional
printing of an oral drug dosage form described herein comprises
designing the oral drug dosage form, in whole or in part, on a
computer system. In some embodiments, the method comprises
inputting parameters of the desired drug release profile and/or an
oral drug dosage form into the computer system. In some
embodiments, the method comprises providing one or more parameters
of the oral drug dosage form, e.g., layer surface area, thickness,
drug mass fraction; erosion rate. In some embodiments, the method
comprises providing the desired drug release profile. In some
embodiments, the methods comprise creating a virtual image of an
oral drug dosage form. In some embodiments, the method comprises
creating a computer model that contains the pre-determined
parameters. In some embodiments, the method comprises feeding the
pre-determined parameters to a three-dimensional printer and
printing an oral drug dosage form according to such pre-determined
parameters. In some embodiments, the method comprises creating a
three-dimensional drawing of an oral drug dosage form based on the
pre-determined parameters of the oral drug dosage form, wherein the
three-dimensional drawing is created on a computer system. In some
embodiments, the method comprises converting, such as slicing, a
three-dimensional drawing of an oral drug dosage form into
three-dimensional printing code, e.g., G code. In some embodiments,
the method comprises using the computer system to execute
three-dimensional printing code, thereby printing an oral drug
dosage form described herein.
[0185] The drug dosage forms disclosed in the present application
can be printed on a commercial scale. For example, in some
embodiments, the methods disclosed herein may be used to 3D print
about 10,000 to about 100,000 tablets of an oral drug dosage form
per hour. In some embodiments, each oral drug dosage form of a
commercial batch possesses or substantially complies with one or
more pre-determined dosage form characteristics described herein,
e.g., printing uniformity, precision of layer thickness(es),
precision of layer surface area, precision of layer active agent(s)
mass fraction, precision of dosage form shape, size, and weight,
precision of active agent(s) amount, and precision of active agent
release profile. In some embodiments, at least about 80%, such as
at least about any of 85%, 90%, or 95%, of oral drug dosage forms
of a commercial batch possess or substantially comply with one or
more pre-determined dosage form characteristics described herein,
e.g., printing uniformity, precision of layer thickness(es),
precision of layer surface area, precision of layer active agent(s)
mass fraction, precision of dosage form shape, size, and weight,
precision of active agent(s) amount, and precision of active agent
release profile.
Methods of ADHD Treatment
[0186] The oral drug dosage forms of the present disclosure are
useful for treating ADHD in an individual. In some embodiments, the
oral drug dosage forms formulated and configured to provide a
sustained release profile of an ADHD non-stimulant and an immediate
release profile of an ADHD stimulant improve patient compliance to
a course of treatment for ADHD.
[0187] In some embodiments, the individual, such as a pediatric
patient, presents difficulties in compliance with scheduled
administration of a traditional pharmaceutical treatment. In some
embodiments, the school or work day (e.g., desire not to take
medicine, desire not to take medicine in front of friends or
colleagues, difficulty remembering to take medicine, etc.) makes
administration of a single drug dosage form in the morning the
preferred method of treatment for increasing treatment
compliance.
[0188] In some embodiments, traditional ADHD stimulant treatments
require a large dose of an ADHD stimulant to provide patient
benefit (e.g., reduced ADHD symptoms, including, but not limited
to, ease of distraction, loss of attention to details,
forgetfulness, loss of focus, boredom, learning disabilities,
difficulty completing projects, problems with listening,
daydreaming, confusion, slow movement, difficulties processing
information, difficulties following instructions, fidgeting,
excessive talking, restlessness, excessive motion, impatience, and
outbursts) throughout the desired time course. Large doses of an
ADHD stimulant used in traditional ADHD stimulant regimes result in
significant side effects such as insomnia, abdominal pain, and loss
of appetite that carry over into the later part of the day or
subsequent days after administration where they become life
disruptive for the individual and those around the individual. In
some embodiments, the oral drug dosage forms of the present
disclosure provide for a reduction of the dose of the administered
active agents, such as an ADHD non-stimulant or ADHD stimulant. In
some embodiments, the oral drug dosage forms of the present
disclosure provide for extended reduction of ADHD symptoms without
detrimental side effects.
[0189] In some embodiments, the present disclosure provides methods
for treating ADHD in an individual in need thereof, the methods
comprising administering to the individual an oral drug dosage form
described herein. In some embodiments, the method for treating ADHD
in an individual in need thereof comprises administering an oral
drug dosage form comprising: (a) an erodible non-stimulant material
admixed with an ADHD non-stimulant; and (b) an erodible stimulant
material admixed with an ADHD stimulant, wherein the erodible
non-stimulant material admixed with the ADHD non-stimulant is
embedded in a substrate material, and wherein upon exposure to
gastrointestinal fluid the ADHD non-stimulant is released according
to a sustained release profile and the ADHD stimulant is released
according to an immediate release profile.
[0190] In some embodiments, the method for treating ADHD in an
individual in need thereof comprises administering to the
individual an oral drug dosage form, wherein the oral drug dosage
form comprises: (a) a multi-layered structure comprising a
plurality of layers of an erodible non-stimulant material admixed
with an ADHD non-stimulant; and (b) an erodible stimulant material
admixed with an ADHD stimulant, wherein the erodible non-stimulant
material admixed with the ADHD non-stimulant is embedded in a
substrate material, and wherein upon exposure to gastrointestinal
fluid the ADHD non-stimulant is released according to a sustained
release profile and the ADHD stimulant is released according to an
immediate release profile. In some embodiments, the multi-layered
structure comprises four layers of an erodible non-stimulant
material admixed with and ADHD non-stimulant. In some embodiments,
the sustained release profile comprises a zero-order release
profile. In some embodiments, the sustained release profile is ADHD
non-stimulant release over about 12 hour. In some embodiments, the
ADHD non-stimulant is one or more of clonidine guanfacine,
atomoxetine, or a prodrug thereof. In some embodiments, the
immediate release profile is ADHD stimulant release of at least
about 85% of the ADHD stimulant in the oral drug dosage form within
15 minutes after oral administration. In some embodiments, the ADHD
stimulant is one or more of methylphenidate (d,l),
dexmethylphenidate, mixed amphetamine salts, dextroamphetamine,
lisdexamfetamine, or a prodrug thereof.
[0191] In some embodiments, the method for treating ADHD comprises
administering an oral drug dosage form described herein based on
the need of the individual. In some embodiments, the oral drug
dosage form is administered once daily. In some embodiments, the
oral drug dosage form is administered twice daily.
[0192] In some embodiments, the individual is an infant (e.g.,
<2 years), child (e.g., 2-12 years), adolescent (e.g., 13-19
years), or adult. In some embodiments, the individual is less than
or about 12 years old, such as about any of 10-12 years old, 8-10
years old, 6-8 years old, 4-6 years old, 2-4 years old, or less
than 2 years old. In some embodiments, the individual is about
13-19 years old, such as about 13-15 years old, 15-17 years old, or
about 17-19 years old. In some embodiments, the individual is older
than about 18 years old, such as about any of 18 years old, 19
years old, 20 years old, 21 years old, 22 years old, 23 years old,
24 years old, 25 years old, 26 years old, 27 years old, 28 years
old, 29 years old, or great than 30 years old.
[0193] In some embodiments, the method for treating ADHD in an
individual further comprises determining a fixed-dose of an ADHD
non-stimulant and an ADHD stimulant for use in an oral drug dosage
form described herein. For example, fixed-doses for treating ADHD
in an individual can be determined by altering the dosage of an
active agent, such as the ADHD non-stimulant and/or the ADHD
stimulant, in a drug dosage form and monitoring the response of the
individual.
[0194] Those skilled in the art will recognize that several
embodiments are possible within the scope and spirit of this
disclosure. The disclosure will now be described in greater detail
by reference to the following non-limiting examples. The following
examples further illustrate the disclosure but, of course, should
not be construed as in any way limiting its scope.
EXAMPLES
Example 1
[0195] This example demonstrates an exemplary oral drug dosage form
formulated and configured to provide a sustained release of an ADHD
non-stimulant and immediate release of an ADHD stimulant.
[0196] As shown in FIG. 2A, an oral drug dosage form was designed
and manufactured to provide sustained release of 0.1 mg of an ADHD
non-stimulant, namely, clonidine, and immediate release of 2.5 mg
of an ADHD stimulant, namely, dextromethylphenidate
(dexmethylphenidate). The sustained release profile of clonidine
provided by the oral drug dosage form is illustrated in FIG. 3.
[0197] The oral drug dosage form designed and manufactured
comprises a multi-layered structure comprising four layers of an
erodible non-stimulant material (79.68:19.92:0.4 weight ratio of
hydroxyl propyl cellulose (HPC), triethyl citrate (TEC), and
clonidine) (FIG. 2A, 210). The total amount of clonidine in the
oral drug dosage form was 0.1 mg. The diameter and thickness of
each layer (from top to bottom) of the multi-layered structure 210
was: (i) diameter 5.2 mm, thickness 0.65 mm; (ii) diameter 4.1 mm,
thickness 0.26 mm; (iii) diameter 2.9 mm, thickness 0.52 mm; and
(iv) diameter 2.4 mm, thickness 0.26 mm.
[0198] The erodible stimulant material admixed with an ADHD
stimulant (79.2:10.8:10 weight ratio of vinylpyrrolidone-vinyl
acetate copolymer (VA64), TEC, and dextromethylphenidate) was
designed as a single-layered structure (FIG. 2A, 225). The total
amount of dextromethylphenidate in the oral drug dosage form was
2.5 mg (propranolol HCl was used as a substitute for
dextromethylphenidate as dextromethylphenidate is a controlled
substance). The dimensions of the single-layered structure were:
diameter 6.8 mm and thickness 0.52 mm.
[0199] The overall dimensions of the oral drug dosage form were:
diameter 8.0 mm and thickness 3.12 mm. The multi-layered structure
comprising clonidine and the single-layered structure comprising
dextromethylphenidate was embedded in a substrate material of
EUDRAGIT.RTM. RSPO (copolymer of ethyl acrylate, methyl
methacrylate, and trimethylammonioethyl methacrylate chloride). The
separation of the multi-layered structure comprising clonidine and
the single-layered structure comprising dextromethylphenidate was
0.52 mm. The substrate material was also used to form a rim 205
that extended 0.52 mm from the top of the multi-layered structure
(the space formed is indicated 215).
[0200] FIG. 2B provides a cross section view of the oral drug
dosage form. As illustrated in FIG. 2B, the directions of erosion
of the multi-layered structure comprising clonidine and the
single-layered structure comprising dextromethylphenidate are
indicated by respective arrows 230, 235.
[0201] The oral drug dosage form was manufactured, namely, produced
using a three-dimensional printing technique, using the settings
provided in Table 1.
TABLE-US-00001 TABLE 1 Three-dimensional printing settings.
Erodible non- Machine barrel 90.degree. C. stimulant material
temperature (multi-layered Connector temperature 95.degree. C.
structure) Printing nozzle 115.degree. C. temperature Pressure 1.2
MPa Substrate material Machine barrel 110.degree. C. temperature
Connector temperature 120.degree. C. Printing nozzle 135.degree. C.
temperature Pressure 0.4 MPa Erodible Machine barrel 100.degree. C.
stimulant material temperature (single-layered Connector
temperature 110.degree. C. structure) Printing nozzle 135.degree.
C. temperature Pressure 1.7 MPa
Example 2
Clinical Pilot Study of Drug Dosage Forms for the Treatment of
ADHD
[0202] A multi-arm clinical study is designed to assess the
efficacy of exemplary drug dosage forms for the treatment of ADHD.
Six primary arms will assess drug dosage forms comprising an ADHD
non-stimulant and an ADHD stimulant. Specifically, the six primary
arms are as follows (1) atomoxetine HCl and dextroamphetamine
sulfate; (2) atomoxetine HCl and dextromethylphenidate HCl; (3)
guanfacine HCl and dextroamphetamine sulfate; (4) guanfacine HCl
and dextromethylphenidate HCl; (5) clonidine HCl and
dextroamphetamine sulfate; and (6) clonidine HCl and
dextromethylphenidate HCl.
[0203] Each primary arm will further assess various dosage
combinations of the ADHD non-stimulant and the ADHD stimulant.
Specifically the following dosages for each active pharmaceutical
ingredient will be assessed: (a) atomoxetine HCl (10, 18, 25, 40,
60, 80, and 100 mg); (b) guanfacine HCl (1, 2, 3, and 4 mg); (c)
clonidine HCl (0.1 and 0.2 mg); (d) dextroamphetamine sulfate (5
and 10 mg); and (e) dextromethylphenidate HCl (2.5, 5, and 10
mg).
[0204] A primary goal of the study is to assess technical
feasibility of the drug dosage forms, including interactions,
stability, cost of goods, and release profiles. A primary goal of
the study is to assess efficacy of the drug dosage forms, including
combinations of an ADHD non-stimulant and an ADHD stimulant, and
dosages thereof.
[0205] Correlative research is performed to determine association
of the combination of an ADHD non-stimulant and an ADHD stimulant
and their respective dosage with improvement of ADHD symptoms.
Categories of ADHD symptoms that will be monitored include, for
example, inattention, hyperactivity, and impulsivity.
[0206] Each individual must have confirmed ADHD.
* * * * *